University of Groningen Copper-catalyzed asymmetric ... · This chapter gives an introduction on copper-catalyzed asymmetric allylic alkylation and ... asymmetric syntheses of the

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Copper-catalyzed asymmetric allylic alkylation and asymmetric conjugate addition in naturalproduct synthesisHuang, Yange

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Copper-catalyzed Asymmetric Allylic Alkylation and Asymmetric

Conjugate Addition in Natural

Product Synthesis

Yange Huang

This Ph.D. thesis was carried out at the Stratingh Institute for Chemistry, University of Groningen, The Netherlands.

The authors of this thesis wish to thank the NRSC-Catalysis for scientific research

funding.

Printed by: Ipskamp Drukkers B.V., Enschede, The Netherlands

RIJKSUNIVERSITEIT GRONINGEN

Copper-catalyzed Asymmetric Allylic

Alkylation and Asymmetric

Conjugate Addition in Natural

Product Synthesis

Proefschrift

ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen

op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op

vrijdag 20 september 2013 om 12.45 uur

door

Yange Huang

Geboren op 1 september 1984

te Taicang, China

Promotores: Prof. dr. B. L. Feringa

Prof. dr. ir. A. J. Minnaard

Copromotor: Dr. M. Fañanás-Mastral

Beoordelingscommissie: Prof. dr. F. J. Dekker Prof. dr. G. Roelfes Prof. dr. J. G. de Vries

ISBN: 978-90-367-6343-1 (book)

978-90-367-6342-4 (electronic)

Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.

-Sir Winston Churchill

To

Yang (my wife) & Xiyuan (my son)

Table of Contents

1. Copper-catalyzed Asymmetric Allylic Alkylation and Asymmetric

Conjugate Addition in Natural Product Synthesis

1

1.1 Introduction 2

1.2 Copper-catalyzed ACA 2

1.2.1 ACA with organozincs 3

1.2.2 ACA with organoaluminum 9

1.2.3 ACA with Grignard reagents 13

1.2.4 ACA with organosilicon reagent 18

1.3 Copper-catalyzed AAA 18

1.3.1 AAA with organozinc reagents 18

1.3.2 AAA with organoaluminum reagents 19

1.3.3 AAA with Grignard reagents 20

1.3.4 AAA with organoboranes 22

1.3.5 AAA with organolithiums 23

1.4 Conclusion 24

1.5 Outline of this thesis 24

1.6 References 25

2. Formal synthesis of (R)-(+)-Lasiodiplodin 29

2.1 Introduction 30

2.2 Biosynthesis of Lasiodiplodin 30

2.3 Previous catalytic asymmetric syntheses 31

2.4 Formal synthesis of (R)-(+)-Lasiodiplodin 33

2.4.1 First retrosynthetic analysis 33

2.4.2 Results and discussion 34

2.4.3 Second retrosynthetic analysis 34

2.4.4 Results and discussion 35

2.5 Conclusion 36

2.6 Experimental Section 36

2.7 References and notes 40

3. A Concise Asymmetric Synthesis of (-)-Rasfonin 43

3.1 Introduction 44

3.2 Previous total syntheses of Rasfonin 44

3.3 Total synthesis of Rasfonin 46

3.3.1 Retrosynthetic analysis 46

3.3.2 Synthesis of upper half of Rasfonin 47

3.3.3 Synthesis of lower half of Rasfonin 48

3.4 Conclusion 53


3.6 References 63

4. A Novel Catalytic Asymmetric Route towards Skipped Dienes with a

Methyl-Substituted Central Stereogenic Carbon

65

4.1 Introduction 66

4.2 Previous methodologies 66

4.3 Synthesis of starting materials 68

4.4 Results of the Cu-catalyzed AAA and discussion 74

4.5 Conclusion 78



5. Towards a Total Synthesis and Structure Elucidation of Phorbasin B 99

5.1 Introduction 100

5.2 Previous synthesis of Phorbasins 100

5.3 First retrosynthetic analysis of Phorbasin B 101

5.4 Results and discussion 102

5.5 Second retrosynthesis of Phorbasin B 104


5.7 Conclusion 108


5.9 References 118

6. Total Synthesis of (S)-(–)-zearalenone 121

6.1 Introduction 122

6.2 Biosynthesis of zearalenone 122

6.3 Previous synthesis of zearalenone 123

6.4 Retrosynthetic analysis 125


6.6 Biological studies 128

6.7 Conclusion 129



Summary

Summary (English) 139

Samenvatting (Nederlands) 143

Acknowledgements 147

Chapter 1

1

Chapter 1

Copper‐Catalyzed Asymmetric Allylic Alkylation

and Asymmetric Conjugate Addition in Natural

Product Synthesis

This chapter gives an introduction on copper-catalyzed asymmetric allylic alkylation and

asymmetric conjugate addition in natural product synthesis. Alternative catalytic

asymmetric syntheses of the natural products prepared by Cu-catalyzed asymmetric

allylic alkylation and asymmetric conjugate addition will also be presented.

Chapter 1

2

1.1 Introduction

Catalytic asymmetric C-C bond forming reactions using organometallic reagents are

among the most important organic transformations.1 The asymmetric conjugate addition

(ACA, Scheme 1, a) and asymmetric allylic alkylation (AAA, Scheme 1, b) are particular

versatile in enantioselective C-C bond forming reactions.2 Especially applying ACA, the

intermediate enolate formed could be further functionalized (Scheme 1, c) by reaction

with other electrophiles (one-pot transformations) introducing to two vicinal

stereocenters. These transformations are frequently applied in the synthesis of complex

biologically active molecules.1 The major part of this chapter is concerned with the

application in the total synthesis of natural products using copper-complex catalyzed

AAA and ACA as the key step.

Scheme 1. General scheme of AAA, ACA and enolate functionalization.

1.2 Copper-catalyzed ACA

Copper-catalyzed ACA of organometallics (Grignard reagents, organozinc reagents,

organoaluminum compounds and organosilicon reagents) to Michael acceptors (cyclic

enones, acyclic enones, nitro-olefins, unsaturated lactones, unsaturated lactams,

dehydropiperidinones, α,β-unsaturated esters, thioesters, amides and imides) has been a

highly active research field in recent decades.3 Since the first discovery of ferrocenyl

ligands such as TaniaPhos and JosiPhos as efficient ligands in the copper-catalyzed ACA

of Grignard reagents, several other chiral ligands were discovered for the

copper-catalyzed ACA including phosphines, phosphoramidites, phosphonites, peptides,

NHC ligands, phosphine-phosphites and aminophosphine ligands.

Chapter 1

3

1.2.1 ACA with organozincs The copper-catalyzed ACA of organozinc reagents has been a longstanding objective in

the field of ACA. A major breakthrough was achieved by the group of Feringa in 1996

based on the development of a BINOL-derived monodentate phosphoramide L1.4

Employing this ligand in the copper-catalyzed ACA of cyclic enones using dialkylzinc

reagents for C-C bond formation was achieved in high yield, chemoselectivity, efficiency

and enantioselectivity. An important feature is that phosphoramide ligands are readily

accessible and due to their modular structure can be readily tuned for a specific

application.5 This methodology was applied in the synthesis of PGE1 methyl ester 6

(Scheme 2) using copper-catalyzed ACA of dialkylzinc 3 to cyclopentenone 1 followed

by trapping with aldehyde 2 as the key step.6 The diastereoselectivity of the aldehyde

trapping was only moderate (threo/erythro=83/17), however, reduction using Zn(BH4)2

followed by separation of the diastereomers gave advanced intermediate 5 as a single

diastereomer with 94% ee. After another 5 steps PGE1 methyl ester 6 was obtained in

high yield. In this way PGE1 methyl ester 6 was obtained in 7% overall yield with 94%

optical purity in 7 steps from 1.

Scheme 2. Total synthesis of PGE1methyl ester 6.

Recently the group of Aggarwal reported a stereocontrolled organocatalytic synthesis of

PGF2α 13 in only 7 steps (Scheme 3).7 Intermolecular aldol reaction catalyzed by 2 mol%

of proline 8 gave product 9 which underwent hemiacetal formation to 10 and an

intramolecular aldol condensation to form α,β-unsaturated aldehyde 11. After acetal

formation product 12 was obtained in 14% overall yield with 98% ee. PGF2α 13 was

prepared in 5 steps from aldehyde 12. In this way PGE2α 13 was obtained in 4% overall

yield with 98% optical purity in 7 steps from 7.

Chapter 1

4

OO

NH

COOH

2 mol%

then[Bn2NH2][OCOCF3] O

O

OHO O

OH

O

O

O OH

O

Intramolecularaldol condensation

O O

O

MeOH

12, 14% based on 798% ee

7

8

9 10 11

HOHO

HO COOH

13

Scheme 3. Total synthesis of PGF2α 13.

In 2001 Hoveyda et al. reported a tandem reaction using the copper-catalyzed ACA of

organozinc to cyclic enones with peptide-based phosphine ligand L2 which is easily

accessible from commercially available components (Scheme 4).8 This methodology was

applied to the synthesis of the natural product, Clavularin B (17). The Zn-enolate formed

by copper-catalyzed ACA using dimethyl zinc was trapped with 4-iodo-1-butene resulted

in cyclic ketone 15 in high yield, ee and chemoselectivity. Silyl enol ether formation

followed by palladium-mediated oxidation (Saegusa–Ito oxidation) of 15 gave

α,β-unsaturated ketone 16. Wacker oxidation of ketone 16 gave the anti-cancer agent,

Clavularin B (17), in only four steps with 42% overall yield. Similar methodology was

applied by the group of Minnaard in the total synthesis of Triglycosyl Phenolic

Glycolipid PGL-tb1199 and PDIM_A 2010 (Scheme 5).

Scheme 4. Total synthesis of Clavularin B (17).

Chapter 1

5

O 1. Cu(OTf)2 (0.5 mol%)L1 (1 mol%), Me2ZnToluene, -25°C, on

2. EtI, HMPA

O

14 1883%, >20:1, 95% ee

O

OH

O

O

O O OMe

O

18

O

O OMeMeO

OMe

O

HO

OMe

HO

19

O

O

18

15

OP N

O

L1

Ph

Ph

O O

22

OO O

19 19

20

Scheme 5. Synthesis of Triglycosyl Phenolic Glycolipid PGL‐tb119 and PDIM_A 20.

Alexakis and coworkers reported a tandem enantioselective conjugate

addition-cyclopropanation to cyclic and linear enones (Scheme 6).11 Copper-catalyzed

ACA using dimethyl zinc with phosphoramidite ligand L3 afforded the Zn-enolate 22

which was following by trapping with TMSOTf. Cyclopropanation of the resulting silyl

enolate gave 23 in excellent yield, moderate dr and with 97% ee. Ring expansion of 23

using FeCl3 resulted in 7-membered ring 24 in 90% yield which was a key intermediate

for the synthesis of (R,S)-Isoclavukerin 25 and (S,S)-Clavukerin 26.

Chapter 1

6

Scheme 6. Formal synthesis of Isoclavukerin and Clavukerin.

The enantioselective total synthesis of Erogorgiane 31 was achieved by the group of

Hoveyda employing a double ACA of Me2Zn to linear enones catalyzed by

(CuOTf)2•C6H6 and peptidic phosphine ligands (L4 and L5) (Scheme 7).12 The first ACA

to enone 27 using only 1 mol% of catalyst derived from ligand L4 gave 28 in 94% yield

and >98% ee, and the product was easily transformed to dienone 29 in a few steps. A

second ACA using 5 mol% of the catalyst derived from ligand L5 provided product 30 in

moderate yield, however, the regioselectivity (1,4/1,6=9/1) and ee (94%) were excellent.

The natural product Erogorgiane 31 was easily prepared from 30. One year later 31 was

also synthesized by Davies and Walji13 by a kinetic enantiodifferentiating step. Product

34 was formed by [Rh2(R-dosp)4]-catalyzed reaction of racemic 32 with diazo ester 33

involving a C-H activation/Cope rearrangement sequence.

Chapter 1

7

Br

O

27

PPh2

N

HN

ONHBu

O

L4 O

Br

O

28, 94%, >98% eeO

O

30, 50 %, 97:3 dr(1,4:1,6 = 9:1)

PPh2

NNHBu

O

Erogorgiane 31

29

L5

Toluene, -15ºC, 48 h Toluene, 4ºC, 24 h

(CuOTf)2-C6H6 (1 mol%)L4 (2.4 mol%), Me2Zn

(CuOTf)2-C6H6 (5 mol%)L5 (12 mol%), Me2Zn

+ CO2Me

N2

[Rh2(S-dosp)4]

23oC

MeO2C

Erogorgiane 31

32 33

34

H

H

MeO2C

+

35

Hoveyda's approach, key step: double ACA

Walji's approach, key step: kinetic enantiodifferentiation

Scheme 7. Total synthesis of Erogorgiane.

In 2004 Feringa et al. reported another example of a domino reaction for the total

synthesis of Pumiliotoxin C (38) (Scheme 8).14 Copper-catalyzed ACA of cyclohexenone

36 using dimethyl zinc provided the zinc enolate which was followed by

palladium-catalyzed allylic substitution with allyl acetate to form ketone 37 in high yield

and dr (trans/cis=8/1) with 96% ee. Ketone 37 was easily transformed to Pumiliotoxin C

(38) in 7 steps. The same natural product was also synthesized enantioselectively by the

group of Helmchen in 2011 by copper-catalyzed ACA with trimethyl aluminum using

ligand L1.15 Diastereomeric products 40 and 41 (40/41=5/1) were isolated in 85%

combined yield. Reductive amination gave (+)-Pumiliotoxin C (38) in 67% yield

and >99 % ee.

Chapter 1

8

O

O

OP N

Ph

Ph

L6

1. Cu(OTf)2 (0.5 mol%)

L6 (1 mol%), Me2Zn, -30oC

2. Pd(PPh3)4 (2 mol%)allyl acetate

O HN

H

H

Pumiliotoxin C (38)36 37

trans/cis=8/196% ee

NHCbz

O

NHCbz

O

H

NHCbz

O

H

+H

HN

H

Pumiliotoxin C (38)67%, >99% ee

39

40

41

OP N

O

L1

Ph

Ph

H2 (30 atm.)Pd(OH)2/Rh/C

MeOH, rt

CuTC (2.2 mol%)L1 (3.8 mol%), AlMe3

Et2O, -30°C, 19 h

85% combined yield

Feringa's approach

Helmchen's approach

Scheme 8. Total synthesis of Pumiliotoxin C.

(R)-Muscone 43, the major odorous constituent of the male musk deer, was synthesized

by the group of Rosini in 2003 (Scheme 9) using copper-catalyzed ACA of dimethyl zinc

to macrocyclic enone 42.16 Employing 3 mol% of copper and 6 mol% of chiral

phosphite ligand L7, (R)-muscone 43 was obtained in 68% yield and 78% ee.

Scheme 9. Total synthesis of Muscone.

Recently the group of Cordova reported a novel catalytic enantioselective β-alkylation of

α,β-unsaturated aldehydes by a combination of transition metal catalysis and

aminocatalysis (Scheme 10).17 Employing copper-PPh3 complex and amine 45, product

46 was obtained in 65% yield with excellent regioselectivity (1,4/1,2=93/7) and ee (94%).

Intermediate 46 was used for the synthesis of three natural products (Curcumene 47,

Dehydrocurcumene 48 and Tumerone 49).

Chapter 1

9

Scheme 10. Total synthesis of Curcumene, Dehydrocurcumene and Tumerone.

A copper-catalyzed ACA of Me2Zn was reported by Carreira et al. in the synthesis of

Daphmanidin E (52) in 2011 (Scheme 11).18 Employing 19 mol% of copper salt and 20

mol% of ligand L8, in a conjugate addition to the nitro olefin moiety in 50, product 51

was obtained in 90% yield with dr = 5:1. Further functionalization led to the natural

product, Daphmanidin E (52).

Scheme 11. Total synthesis of Daphmanidin E.

1.2.2 ACA with organoaluminum

Besides organozinc reagents, organoaluminum compounds are frequently used in natural

product synthesis. In 2007 excellent methodology to construct chiral quaternary center

was developed by the group of Alexakis using copper-catalyzed ACA of

trialkylaluminum reagents to cyclic enones (Scheme 12).19 Employing 5 mol% of CuTC

and 10 mol% of ligand L9, product 54 was isolated in 81% yield and 95% ee.

HCl-promoted hydrolysis of the acetal and in situ intramolecular cyclization gave 55

which was used for the preparation of Axane core structure 56.

Chapter 1

10

Scheme 12. Synthesis of Axane core structure 56.

Recently Hoveyda et al. reported a NHC-copper catalyzed ACA to cyclic enones using

Si-containing vinylaluminum reagent 61 to install a chiral quaternary center (Scheme

13).20 Subsequently this method was applied in the synthesis of Riccardiphenol B (59).

Employing 5 mol% of CuCl2 and 2.5 mol% of 60 (dimeric NHC-Ag complex), product

58, after trapping using acetic anhydride, was isolated in 67% yield and excellent 96% ee.

Riccardiphenol B (59) was obtained in only two steps from 58.

Scheme 13. Total synthesis of Riccardiphenol B.

In 2008 Feringa and coworkers reported a total synthesis of Myrtine (Scheme 14) using

the copper-catalyzed ACA of N-Boc-2,3-dehydro-4-piperidone 62 with trimethyl

aluminum and ligand L10.21 Product 63 was obtained in high yield and 96% ee. Further

transformation of 63, after 3 steps, resulted in Myrtine 64 in 14% overall yield. Recently

the groups of Pozo22 and Hong23 have reported the synthesis of the same molecule by

applying an organocatalytic aza-Michael reaction to install the piperidine ring 67 and 70,

respectively, with excellent yield and ee.

Chapter 1

11

Scheme 14. Total synthesis of Myrtine.

In 2008 the first catalytic enantioselective total synthesis of Clavirolide C (77) was

achieved by the group of Hoveyda (Scheme 15).24 For the preparation of the chiral

building block 73, a copper-catalyzed ACA of dimethyl zinc to substrate 71 with only 1

mol% of copper and 2.5 mol% of ligand L11 was used, providing pyranone 72 in

excellent yield and ee. For the synthesis of building block 75, NHC•Cu-catalyzed ACA to

74 using trimethyl aluminum was employed followed by silyl enol ether formation using

Et3SiOTf to provide 75 in 72% yield and 84% ee. Subsequent aldol reaction with

aldehyde 73 gave 76 as a mixture of diastereomers which was transformed into

Clavirolide C (77).

Chapter 1

12

Scheme 15. Total synthesis of Clavirolide C.

Recently the group of Endo and Shibata reported the first case of copper-catalyzed ACA

of organoaluminum to linear α,β-unsaturated amides and applied this ACA in the

synthesis of several natural products (Scheme 16).25 ACA on substrate 79 using Cu(OTf)2

and ligand L11 gave 80 in moderate yield, however, with excellent 96% ee. Product 80

was readily transformed into (S)-Florhydral 81 in three steps. For the formal synthesis of

Tumerone 85 and Deoxyanisatin 84, substrate 82 was used with Cu(OTf)2 and ligand L12

and conjugate addition product 83 was obtained in excellent yield and ee. Similar results

were achieved with substrate 86 using Cu(OAc)2 and ligand L13. Frondosin B (88) could

be easily prepared from adduct 87 in 4 steps.

Chapter 1

13

Me

N

O

82 Me

N

O

Me

O

(+)-ar-Tumerone 85

Cu(OTf)2 (5 mol%)L12 (10 mol%)

Me3Al, THF, rt, 2 h

83, 87%, 97% eeHO HO

OH

O

OO

O

8-Deoxyanisatin 84

O

NO

MeO

Cu(OAc)2 (10 mol%)L13 (10 mol%)

Me3Al , THF, 2 h

O

NO

MeO

8687, 82%, 94% ee

HO

O

Frondosin B 88

OH

OH

Ph2P

Ph2PL13

OH

OH

PAr2

L11 Ar = PhL12 Ar = 3,5-(CF3)2C6H3

N

O

79

Cu(OTf)2 (5 mol%)L11 (10 mol%)

Me3Al, THF, rt, 2 hN

O

80, 54%, 96% ee

O

(S)-Florhydral 81

Scheme 16. Formal synthesis of Florhydral, Tumerone, Deoxyanisatin and Frondosin B.

An elegant application of copper-catalyzed ACA of an organoaluminum reagent was

recently reported by Baran et al. in the synthesis of taxane 91 using Alexakis’

methodology (Scheme 17).26 Employing 2 mol% of CuTC and 4 mol% of ligand L14,

intermediate 90 with the key quaternary stereocenter present in taxane was isolated in

excellent yield and ee. Further functionalization of 90 gave taxane 91 in good yield.

Scheme 17. Synthesis of taxane 79.

1.2.3 ACA with Grignard reagents

A significant breakthrough was reported by Feringa and coworkers with the development

of a highly enantioselective copper-catalyzed ACA with Grignard reagents.27 This has

Chapter 1

14

been a longstanding objective in catalytic asymmetric C-C bond formation as the

organomagnesium reagents are versatile organometallic reagents. Subsequently this

methodology was applied in the synthesis of several natural products. In the total

synthesis of Phaseolinic acid 95 (Scheme 18),28 copper-catalyzed ACA of ester 92 using

methylmagnesium bromide and ligand L15 resulted in magnesium enolate 93 which was

trapped by hexanal afforded 94 in high yield and excellent dr and ee. Phaseolinic acid 95

was conveniently prepared from 94 in only 2 steps.

Scheme 18. Total synthesis of Phaseolinic Acid.

Recently Feringa and Minnaard reported a total synthesis of Rasfonin 100 using iterative

ACA (Scheme 19).29 Important features are the low catalyst loading (1 mol%), the

catalytic reaction can be performed up to 40 g scale and the discovery of JosiPhos L15 as

the most effective ligand which is commercial available. The first ACA product 97 was

achieved in 95% yield and 96% ee. Excellent results were also obtained for the second

addition product 99 (86% yield and >95/5 dr). The same methodology was applied by the

groups of Minnaard and Feringa in the synthesis of several natural products including

Borrelidin, Phthioceranic acid, Mycocerosic acid, Mycolipenic acid, β-D-Mannosyl

Phosphomycoketide, PDIMA, apple leafminer pheromones, Lardolure and

sulfoglycolipid Ac2SGL.30 Several alternative asymmetric synthesis of Rasfonin 100 have

reported. The synthesis by the group of Boeckman in 2006 is based on the use of

camphor lactam chiral auxiliaries (106a, 106b, 106c) in order to allow the synthesis of

different stereoisomers.31 The oxazaborolidine catalyst 107 was applied in the key

assembly of butenolide 104 via an asymmetric vinylogous Mukaiyama aldol addition.

Recently, the group of Nanda32 reported a chemoenzymatic asymmetric synthesis of

Rasfonin 100. Enantioselective enzymatic desymmetrization (EED) and Gluconobacter

oxydans mediated oxidative kinetic resolution (OKR) were used for the introduction of

three stereocenters.

Chapter 1

15

OO

O

OOH

OH

TBDPSO

O

SEtCuBr-SMe2 (1 mol%)JosiPhos L15 (1.1 mol%)

TBME, -78oC, 16h

95%, 96%ee

TBDPSO

O

SEtTBDPSO

O

SEt

CuBr-SMe2 (1 mol%)JosiPhos L15 (1.1 mol%)

TBME, -78oC, 16h

86%, dr>95/5

TBDPSO

O

SEt

Fe

(R,S) -Josiphos L15

PPh2

PCy2

100

96 97 98

99

Feringa and Minnaard's route, key step: Cu-catalyzed iterative ACA

N

O

O

NH

O

106a

N

O

O O

O

TMSO

107

NB

HAr

Ar

o-tolH

TfO

107

OH

OO

10481%, threo/erythro=20/1

dr 20/1

OO

OH

1. LiAlH4

2. NWO, TPAP

NH

106b

NH

O

106cO

Rasfonin 100

101 102 103

105

Boeckman's routekey steps:camphor lactam chiral auxiliaryasymmetric vinylogous Mukaiyama based alkylation

TBSOOH

HO

TBSOOH

AcO OTBS

OTBS

HO

O

99% ee

AcO OAc HO OAc

11286%, ee>99%

TBSO OH

TBSO OH

TBSO OH

O

Rasfonin 100

10991%, ee>99%

11445%, 96% ee

Nanda's route, key elements: enantioselective enzymatic desymmetrizationoxidative kinetic resolution

108110

111113

115

EED

EED OKR

Scheme 19. Total synthesis of Rasfonin.

Chapter 1

16

O

OEt

O

(S)-BINAP-Ru(II)MeOH, 6 atm H2

100oC, 92% OH

OEt

O OTBS

O Ipc2B

Et2O, -90oC81%

OTBS

OH

OTBS

OMe

O N

NH

O

-TFA

Hantzch esterCHCl3, 80%

OTBS

OMe

O

OO

OMe

O O O

NO

HN

MeO

O

(+)-Neopeltolide 120

MTBE, -78ºC

Pr

OMeO

OTBS

Pr

TBSO R O

OMe

116

Pr

TBSO R

SEt

O

118

Pr

TBSO R

SEt

O

[Rh(cod)2]OTf (5 mol%)L16 (10 mol%)

Me2PhSi-Bpin, Et3N

1,4-Dioxane/H2O, 45ºC117

(Mismatched product)55%, anti, 90% de

R = SiMe2Ph

PPh2

PPh2

L16

119 (Matched product)90%, anti,anti, 90% de

FePh2P

Cy2P

L17

CuBr-SMe2 (5 mol%)L17 (6 mol%)MeMgBr

Oestreich's route, key steps: iterative catalytic asymmetric conjugate silyl transfer reactionCu-catalyzed ACA

(+)-Neopeltolide 120

121 122 123

124

125

126

127128

Paterson's route, key steps: catalytic asymmetric hydrogenation and organocatalytic asymmetric reduction

Scheme 20. Synthesis of Neopeltolide.

Several catalytic asymmetric syntheses of Neopeltolide 120 were described. The group of

Oestreich33 reported an iterative catalytic asymmetric conjugate silyl transfer reaction for

the synthesis of one important intermediate of Neopeltolide 120 (Scheme 20).

Rhodium-catalyzed ACA of 116 using BINAP L16 as the ligand gave the mismatched

product 117 in 55% yield and excellent 90% de. Subsequent copper-catalyzed ACA of

118 derived from 117 resulted in matched product 119 in high yield and ee which could

be used for the synthesis of Neopeltolide 120. Catalytic asymmetric hydrogenation and

organocatalytic asymmetric reduction (transition metal catalysis and organocatalysis)

Chapter 1

17

were applied for the synthesis of stereogenic centers in Paterson’s total synthesis.34

Asymmetric allylation using chiral allyl borane was used for the introduction of the

stereogenic centers in the Sasaki’s route.35

Scheme 21. Total synthesis of natural sulfated alkene 137.

Besides the application of 1,4-ACA in natural product synthesis, Feringa et al. also

applied the 1,6-ACA in the total synthesis of natural sulfated alkene 137 (Scheme 21).36

Employing 2 mol% of Cu-catalyst based on chiral ligand L18 and Grignard reagent 135,

product 136 was formed in moderate yield, however, with excellent regioselectivity

(1,6/1,4=94/6) and ee. The final natural product, sulfated alkene 137, could be easily

obtained from intermediate 137 in 3 steps.

Scheme 22. Formal synthesis of Spirovibsanin A.

For the formation of chiral quaternary centers Alexakis and coworkers developed a novel

NHC-copper catalyzed ACA of cyclic enones using Grignard reagents in 2010 which was

a major improvement compared to their earlier discovery of the ACA of

trimethylaluminum (Scheme 22).37 Subsequently this methodology was employed in the

formal synthesis of Spirovibsanin A (140). Employing 3 mol% of Cu(OTf)2 and 4 mol%

of ligand L19, chiral cyclohexanone 139 was isolated in good yield and with high ee.

Chapter 1

18

1.2.4 ACA with organosilicon reagent Copper-catalyzed ACA of organosilicon reagents was used in natural product synthesis in

a few cases. In 2012 Hoveyda and co-workers reported a NHC-Cu catalyzed

enantioselective conjugate silyl addition to cyclic and acyclic enones with excellent yield

(up to 97%) and ee (up to 98%) (Scheme 23).38 Subsequently they applied the

methodology in the synthesis of an important intermediate 142 of Erysotramidine 143

using a one-pot procedure (conjugate addition-enolate alkylation).

Trans-α,β-disubstituted cyclohexanone 142 was obtained in 92% yield, >98/2 dr and

97.5/2.5 er. From this intermediate Erysotramidine 143 could be prepared according to

Stalke’s route.39

Scheme 23. Synthesis of intermediate 142 for Erysotramidine.

1.3 Copper catalyzed AAA

The copper-catalyzed AAA constitutes an attractive and versatile approach to a variety of

chiral building blocks especially when using organometallic reagents to form product

with allylic stereogenic centers. 40 Since the first copper-catalyzed AAA of Grignard

reagents with allylic acetates reported by Bäckvall and van Koten,41 other organometallic

reagents (organozinc reagents, organoaluminum reagents, organoboranes and

organolithium reagents) have been applied successfully for this C-C bond formation.

Besides acetates, chlorides, bromides and phosphates are frequently used leaving groups.

The use of organolithium reagents allowed the use of allylic ethers as efficient substrates

for copper-catalyzed AAA as reported by the group of Feringa recently.56 Chiral ligands

frequently used are phosphoramidites, peptides, NHC ligands and ferrocene ligands.

1.3.1 AAA with organozinc reagents Since the breakthrough achieved by Knochel in 1999 who applied bulky organozinc as

the nucleophile in the SN2’ displacement of allylic chloride,42 organozinc reagents are

frequently applied in copper-catalyzed AAA. As early as 2001 Hoveyda et al. reported a

copper-catalyzed AAA using dialkylzinc reagents to form quaternary stereogenic

centers.43 This methodology was applied in the synthesis of natural product

(R)-Sporochnol 146 (Scheme 24). Employing 10 mol% of CuCN and 10 mol% of ligand

Chapter 1

19

L21 using organozinc reagent 145, the allylic alkylation was followed by hydrolysis of

the tosyl group to provide Sporochnol 146 in 82% overall yield and 82% ee. A phosphate

was applied as leaving group in this case.

Scheme 24. Synthesis of Sporochnol.

Subsequently a Cu-catalyzed AAA to prepare α-alkyl-β,γ-unsaturated esters was

developed (Scheme 25).44 Employing 5 mol% of copper and 10 mol% of ligand L22,

product 148 was prepared in 80% yield with excellent regioselectivity and ee. Elenic acid

151 was easily prepared from product 148 in two steps by alkene metathesis using 149

followed by ester hydrolysis and ether cleavage.

Scheme 25. Synthesis of Elenic Acid 151.

1.3.2 AAA with organoaluminum reagents Besides organozinc reagents, organoaluminum compounds are frequently applied in

natural product synthesis involving asymmetric allylic alkylation as key step. In 2007

Hoveyda et al. reported a total synthesis of (+)-Baconipyrone C (157) using NHC-Cu

catalyzed double-asymmetric allylic alkylation of substrate 153 (Scheme 26).45

Employing 15 mol% of copper and 7.5 mol% of ligand L23, product 156 was isolated in

61% yield with excellent >98% ee.

Chapter 1

20

Scheme 26. Total synthesis of Baconipyrone C.

The same group also achieved the synthesis of Nyasol 161 (Scheme 27) using a

copper-catalyzed AAA with trisubstituted vinylaluminum reagent 159.46 Employing 2

mol% of CuCl2 and 1 mol% of ligand L24 with aluminum reagent 159, chiral 1,4-diene

160 (>98% E) was formed in 76% yield with excellent regioselectivity (>98 SN2’) and ee

(97%). Further conversion of 160 which includes proto-desilylation with trifluoroacetic

acid led to Nyasol 161 in high yield.

Scheme 27. Total synthesis of Nyasol 161.

1.3.3 AAA with Grignard reagents Copper-catalyzed AAA of Grignard reagents are frequently used in natural product

synthesis. Recently the group of Feringa reported a formal synthesis of Lasiodiplodin

(Scheme 28) using Cu-catalyzed AAA. 47 Employing 1 mol% of copper and 1.1 mol% of

ligand L25, allylester 163 was obtained in excellent yield and 99% ee. The Lasiodiplodin

precursor 164 could be synthesized in several steps from 163. An alternative catalytic

Chapter 1

21

asymmetric synthesis of Lasiodiplodin was reported by Jones and Huber using

chromium-catalyzed enantioselective addition of dimethyl zinc to an aldehyde (86% ee)

as a key step.48

Scheme 28. Formal synthesis of Lasiodiplodin.

Feringa and co-workers also reported a catalytic asymmetric synthesis of naturally

occurring butenolides via hetero-AAA followed by ring closing metathesis (Scheme

29).49 Employing 3 mol% of copper bromide dimethyl sulfide complex and 3.6 mol% of

ligand L26, Cu-catalyzed hetero-AAA of 126 with different Grignard reagents afforded

allyl ester 166 in excellent yield and high ee. These chiral intermediates could be readily

transformed into different natural butenolides (Whiskey Lactone 169, Cognac Lactone

170, Nephrosteranic Acid 167 and Roccellaric Acid 168). Similar methodology was

applied by the group of Minnaard for the total synthesis of Ac2SGL.30h Previously

catalytic asymmetric synthesis of Whiskey Lactone 169 was reported by Bruckner using

asymmetric Sharpless dihydroxylation as the key step.50

Scheme 29. Synthesis of natural occurring butenolides.

Recently the Feringa group developed a copper-catalyzed AAA with allyl Grignard

reagents (Scheme 30).51 Starting from allyl bromides 171 and 174 and allyl Grignard

Chapter 1

22

using 5 mol% of (CuOTf)•C6H6 and 6 mol% of ligand L1, bisallyl compound 172

(precursor for Sabinene 173) and 175 were formed with high yield, regioselectivity and

ee. The Martinelline alkaloids chromene derivative core 176 was prepared from 175 with

92% ee.52

Scheme 30. Cu‐catalyzed allyl‐allyl cross coupling.

1.3.4 AAA with organoboranes Copper-catalyzed AAA of vinylboron reagents were recently reported by the group of

Hoveyda and applied in the synthesis of Pummerer ketones 180 and 181 (Scheme 31).53

Starting from allyl phosphates 177 and vinyl borane 178, α,β-unsaturated aldehyde 179,

after hydrolysis of the acetal group, was obtained in 77% yield, >98% SN2’ and 96% ee.

Pummerer ketone 180 and anti- Pummerer ketone 181 were prepared from 179 in 4 steps.

Scheme 31. Synthesis of Pummerer ketone and anti‐ Pummerer ketone.

In 2012 the Hoveyda group achieved the formal synthesis of Cuparenone by NHC-Cu

catalyzed AAA of alleneboron reagent 183 (Scheme 32). Product 184 was obtained in

83% yield and 84% ee.54 Copper-catalyzed hydroboration using ligand L29 followed by

oxidation afforded 186 in good yield. α-Cuparenone 187 could be easily prepared from

Chapter 1

23

186 in 3 steps. In the same year the group of Minnaard reported a synthesis of

α-Cuparenone in only 2 steps via a palladium catalyzed asymmetric conjugate reaction of

cyclopentenone 188 with p-tolyl boronic acid.55

Scheme 32. Formal synthesis of Cuparenone.

1.3.5 AAA with organolithiums In 2012 the group of Feringa developed a copper-catalyzed AAA of acyclic allylic ethers

with organolithium reagents (Scheme 33).56 This methodology was applied in the shortest

enantioselective synthesis of (S)-Arundic acid 193. Employing 5 mol% of CuTC and 11

mol% of ligand L30 provided chiral olefin 192. Ozonolysis and subsequently aldehyde

oxidation gave (S)-Arundic acid 193 in 61% overall yield and >98% ee over 5 steps

sequence from benzylether 191. (S)-Arundic acid 193 was also synthesized by the group

of the Cozzi57 by enantioselective α-alkylation of aldehyde 195 with

1,3-benzodithiolylium tetrafluoroborate 194 using MacMillan catalyst 197.

Chapter 1

24

Scheme 33. Synthesis of Arundic acid 193.

1.4 Conclusion

In this chapter a brief overview of copper-catalyzed AAA and ACA in natural product

synthesis is given. These two catalytic C-C bond forming reactions have shown to be

highly versatile and selective steps for the enantioselective construction of complex

natural molecules. Due to the broad substrate scope, variety of chiral ligands, readily

available organometallic reagents and excellent enantioselectivity of these two reactions,

it can be concluded that these methodologies are highly versatile and it is expected that

these methods will become more popular in natural product synthesis in the future.

1.5 Outline of this thesis

In this thesis, copper-catalyzed asymmetric allylic alkylation and asymmetric conjugate

addition are described in the total synthesis of several biologically active molecules

(Lasiodiplodin, Rasfonin and Zearalenone). A second part of this thesis aims at the

development of a novel catalytic asymmetric route towards skipped dienes with a methyl

substituted central stereogenic carbon using copper-catalyzed AAA and its application in

the total synthesis of natural product, Phorbasin B.

In chapter 2, the formal catalytic asymmetric synthesis of Lasiodiplodin is described. The

Chapter 1

25

copper-catalyzed AAA of Grignard reagents is applied for the introduction of the

stereogenic center. Subsequently RCM and sp3-sp2 Suzuki coupling are used for the

synthesis of the macrocyclic structure of the natural product.

In chapter 3, the catalytic asymmetric synthesis of Rasfonin is presented. An iterative

copper-catalyzed ACA of Grignard reagent and stereospecific Achmatowicz

rearrangement are the key strategic steps in this synthesis.

In chapter 4, a novel catalytic asymmetric route towards skipped dienes with a methyl

substituted central stereogenic carbon by a copper-catalyzed AAA is shown. This

transformation leads to important chiral 1,4-diene building blocks with excellent regio-

and enantioselectivity (ee values up to 99%; SN2’/SN2 ratio up to 97:3) in nearly all cases.

In chapter 5, the asymmetric total synthesis of Phorbasin B is presented. A

copper-catalyzed AAA of Grignard reagents, as described in chapter 4, is applied for the

introduction of the side chain. Evans aldol reaction is used for the construction of the

cyclohexenone ring.

Finally in chapter 6, the catalytic asymmetric synthesis of Zearalenone is described. The

copper-catalyzed AAA of a Grignard reagent is the key strategic step in this synthesis.

Biological studies of Zearalenone led to the identification of a novel lipoxygenases

inhibitor.

1.6 Reference

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Springer-Verlag: Berlin, 1999. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;

John Wiley and Sons; New York, 1994. (c) Blaser, H.-U.; Schmidt, E. Asymmetric Catalysis

on Industrial Scale: Challenges, Approaches and Solutions; Wiley-VCH; Weinheim, 2004.

2. (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon; Oxford,

1992. (b) Krause, N. Modern Organocopper Chemistry; Wiley-VCH Verlag GmbH;

Weinheim, 2002. (c) Pfaltz, A.; Lautens, M. Allylic Substitution Reactions. In Comprehensive

Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:

Berlin, 1999; p 833. (d) Tomioka, K.; Nagaoka, Y. Conjugate Addition of Organometallic

Reagents. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,

Eds.; Springer-Verlag: Berlin, 1999; p 1105. (e) Paquin, J.-F.; Lautens, M. Allylic Substitution

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Chapter 1

26

Yamamoto, H., Eds.; Springer-Verlag: Berlin Heidelberg, 2004; p 73. (f) Tomioka K.

Conjugate Addition of Organometals to Activated Olefinics. In Comprehensive Asymmetric

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Shibata, T. Synthesis, 2012, 44, 1427; (g) Beller, M.; Bolm, C. Transition metals for organic

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Galestokova, Z.; Sebesta, R. Eur. J. Org. Chem. 2012, 6688–6695.

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Angew. Chem. Int. Ed. 1997, 36, 2620–2623.

5. Teichert, J. F.; Feringa, B. L. Angew. Chem. Int. Ed. 2010, 49, 2486-2528.

6. Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841.

7. Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature, 2012, 489, 278.

8. Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755–756.

9. Barroso, S.; Castelli, R; Baggelaar, M. P.; Geerdink, D.; ter Horst, B.; Casas-Arce, E.;

Overkleeft, H. S.; van der Marel, G. A.; Codée, J. D. C.; Minnaard, A. J. Angew. Chem. Int. Ed.

2012, 51, 11774.

10. Casas-Arce, E.; ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem. Eur. J. 2008, 14, 4157.

11. Alexakis, A.; March, S. J. Org. Chem. 2002, 67, 8753.

12. Cesati, R. R.; de Armas J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 96.

13. Davies, H. M. L.; Walji, A. M. Angew. Chem. Int. Ed. 2005, 44, 1733 –1735.

14. Dijk, E. W.; Panella, L.; Pinho, P.; Naasz, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L.

Tetrahedron, 2004, 60, 9687.

15. Gärtner, M.; Qu, J.; Helmchen, G. J. Org. Chem. 2012, 77, 1186.

16. Scafato, P.; Labano, S.; Cunsolo G.; Rosini, C. Tetrahedron: Asymmetry, 2003, 14,

3873–3877.

17. Afewerki, S,; Breistein, P.; Pirttila, K.; Deiana, L.; Dziedzic, P.; Ibrahem, I.; Cordova, A.

Chem. Eur. J. 2011, 17, 8784–8788.

18. Weiss, M. E.; Carreira, E. M. Angew. Chem. Int. Ed. 2011, 50, 11501.

19. Alexakis, A.; Vuagnoux-d´Augustin M. Chem. Eur. J. 2007, 13, 9647.

20. May, T. L.; Dabrowski J. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 736.

21. Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2008, 6, 3464.

Chapter 1

27

22. Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Flores, S.; Guerola, M.; del Pozo, C.

Tetrahedron, 2011, 67, 7412–7417.

23. Ying, Y.; Kim, H.; Hong, J. Org. Lett. 2011, 13, 796–799.

24. Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 12904.

25. Endo, K.; Hamada, D.; Yakeishi, S.; Shibata, T. Angew. Chem. Int. Ed. 2013, 52, 606.

26. Mendoza, A.; Ishihara, Y.; Baran, P. S. Nature Chem. 2012, 4, 21.

27. Feringa, B. L.; Badorrey, R.; Pena, D.; Harutyunyan, S. R.; Minnaard, A. J. Proc. Natl. Acad.

Sci. USA, 2004, 101, 5834–5838.

28. Howell, G. P.; Fletcher, S. P.; Geurts, K.; ter Horst, B.; Minnaard, A.J.; Feringa B. L. J. Am.

Chem. Soc. 2006, 128, 14977.

29. Huang, Y.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2012, 10, 29.

30. For Borrelidin see: (a) Madduri, A. V. R.; Minnaard, A.J. Chem. Eur. J. 2010, 16, 11726. For

Phthioceranic Acid see: (b) ten Horst, B.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2007, 9,

3013. For Mycocerosic acid see: (c) ten Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem.

Commun. 2007, 489. For Mycolipenic acid see: (d) ten Horst, B.; van Wermeskerken, J.;

Feringa, B. L.; Minnaard, A. J. Eur. J. Org. Chem. 2010, 38. For β-D-Mannosyl

Phosphomycoketide see: (e) van Summeren, R. P.; Moody, D. B.; Feringa, B. L.; Minnaard, A.

J. J. Am. Chem. Soc. 2006, 128, 4546. For PDIM A see reference 10. For apple leafminer

pheromones see: (f) van Summeren, R. P.; Reijmer, S. J. W.; Feringa, B. L.; Minnaard, A. J.

Chem. Commun. 2005, 1387. For Lardolure see: (g) Des Mazery, R.; Pullez, M.; López, F.;

Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966. For

sulfoglycolipid Ac2SGL see: (h) Geerdink, D.; ter Horst, B.; Lepore, M.; Mori, L.; Puzo, G.;

Hirsch, A. K. H.; Gilleron, M.; de Libero, G.; Minnaard, A. J. Chem. Sci. 2013, 4, 709.

31. Boeckman, R. K. Jr.; Pero, J. E.; Boehmler, D. J. J. Am. Chem. Soc., 2006, 128, 11032.

32. Bhuniya, R.; Nanda, S. Tetrahedron, 2013, 69, 1153-1165.

33. Hartmann, E.; Oestreich, M. Angew. Chem. Int. Ed. 2010, 49, 6195.

34. Paterson, I.; Miller, N. A. Chem. Commun. 2008, 4708–4710.

35. Fuwa, H.; Saito, A.; Naito, S.; Konoki, K.; Yotsu-Yamashita, M.; Sasaki, M. Chem. Eur. J.

2009, 15, 12807 – 12818.

36. den Hartog, T.; Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int.

Ed. 2008, 47, 398.

37. Kehrli, S.; Martin, D.; Rix, D.; Mauduit, M.; Alexakis, A. Chem. Eur. J. 2010, 16, 9890.

38. Lee, K.; Hoveyda, A. H. J. Am. Chen. Soc. 2010, 132, 2898–2900.

39. Tietze, L. F.; Tolle, N.; Kratzert, D.; Stalke, D. Org. Lett. 2009, 11, 5230–5233.

40. For reviews in allylic alkylation, see: (a) Endo, K.; Shibata, T. Synthesis, 2012, 44, 1427; (b)

Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev.

2008, 108, 2824; (c) Alexakis, A.; Malan, C.; Lea, L.; Tissot-Croset, K.; Polet, A.; Falciola, C.

Chapter 1

28

Chimia, 2006, 60, 124.

41. (a) Van Klaveren, M.; Persson, E. S. M.; del Villar, A.; Grove, D. M.; Bäckvall, J. E.; van

Koten, G. Tetrahedron Lett. 1995, 36, 3059. (b) Karlstrom, A. S. E.; Huerta, F. F.; Meuzelaar,

G. J.; Bäckvall, J. E. Synlett 2001, 923. (c) Cotton, H. K.; Norinder, J.; Bäckvall, J. E.

Tetrahedron 2006, 62, 5632.

42. Dubner, F.; Knochel, P. Angew. Chem. Int. Ed. 1999, 38, 379–381.

43. Luchaco-Cullis, C. A.; Mizutani, K. E. M.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40,

1456.

44. Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690.

45. Gillingham, D.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2007, 46, 3860.

46. Akiyama, K.; Gao, F.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2010, 49, 419.

47. Huang, Y.; Minnaard, A. J.; Feringa, B. L. Synthesis, 2011, 1055–1058.

48. Jones, G. B.; Huber, R. S. Synlett, 1993, 367.

49. Mao, B.; Geurts, K.; Fañanás-Mastral, M.; van Zijl, A.W.; Fletcher, S.P.; Minnaard, A. J.;

Feringa, B. L. Org. Lett. 2011, 13, 948.

50. Harcken, C.; Bruckner, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 2750.

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2140–2143.

52. Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 10014.

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54. Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490.

55. Gottumukkala, A. L.; Matcha, K.; Lutz, M.; de Vries, J. G.; Minnaard, A. J.; Chem. Eur. J.

2012, 18, 6907 – 6914.

56. Pérez, M.; Fañanás-Mastral, M.; Hornillos, V.; Rudolph, A.; Bos, P. H.; Harutyunyan, S. R.;

Feringa, B. L. Chem. Eur. J. 2012, 18, 11880 – 11883.

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7842–7846.

Chapter 2

29

Chapter 2

Formal Synthesis of (R)‐(+)‐Lasiodiplodin

In this chapter the catalytic asymmetric formal synthesis of (R)-(+)-Lasiodiplodin is

described. Copper-catalyzed asymmetric allylic alkylation is the key strategic element in

this synthesis.

Parts of this chapter have been published: Y. Huang, A. J. Minnaard, B. L. Feringa, Synthesis, 2011, 1055-1058.

Chapter 2

30

2.1 Introduction

Important bioactive compounds, such as resorcylic acid lactones (RALs) which are

closely related to salicylic acid derivatives, are popular synthetic targets since several

natural products of this type were identified as pharmacophores (Figure 1). For example,

(S)-Zearalenone exhibits antibacterial, uterotropic and anabolic activity,1 and recently we

found it’s a moderately active lipoxygenase inhibitor.2 Zeranol, a nonsteroidal livestock,

including beef cattle, growth-promoting antagonist, is in clinical trials for the treatment of

(post)menopausal syndrome.3 Pochonin C has shown inhibition in the herpes simplex

virus (HSV) replication.4 Aigialomycin D was discovered to possess antimalarial

activity.5 Lasiodiplodin 1, which was isolated from the fungus Botrysdiplodia

theobromae and the wood of Euphorbia splendens and E. fidjiana, displays antileukemia

activity.6 And its demethylated congener 2, a secondary metabolite found in Chinese

traditional medicine, efficiently inhibits prostaglandin biosynthesis.7

Figure 1. Bioactive resorcylic acid lactones.

2.2 Biosynthesis of Lasiodiplodin

The primary metabolites are a kind of metabolite including nucleic acids, proteins,

carbohydrates and fats which are directly involved in living, growth and reproduction of

all organisms. The secondary metabolites, on the other hand, are not involved in these

processes and their presence is restricted in nature. The natural functions of most

secondary metabolites are not clear yet, however, they are often involved in defending

against predators. And most biologically active molecules are secondary metabolites.8

Chapter 2

31

SCoA

O

5 x

S

O

HOPKS-R

Malonyl-CoA x 3

Aldol Condensation

OH

HO

HO

S O

NR-PKS

cyclization

OH

HO

O

O

o-methylation

O

HO

O

O

1

3 4 5

2

Figure 2. Proposed biosynthesis pathway to 1.9

According to recent work from the group of Nabeta,9 Lasiodiplodin 1 and its

demethylated congener 2 are synthesized via a polyketide biosynthetic pathway in L.

Theobromae, similar to other resorcylic acid lactones (Figure 2). Condensation of 5

acetyl-CoA catalyzed by R-PKS gave the intermediate 4. The acyl chain was transferred

to NR-PKS which was followed by condensation with 3 malonyl-CoA molecules and one

aldol condensation to give a resorcylyl intermediate 5. NR-PKS then catalyzed the

cyclization to form the macrolactone. Finally, O-methylation of the hydroxyl group gave

Lasiodiplodin 1.

2.3 Previous catalytic asymmetric syntheses

Many of the synthetic routes to Lasiodiplodin 1 either lead to the racemate10 or are based

on chiral starting materials11 or on chiral auxiliaries.12 The first catalytic asymmetric

synthesis of (R)-(+)-Lasiodiplodin was reported by Jones and Huber (Figure 3).13 In their

synthesis the key step was an enantioselective addition of dimethyl zinc to aldehyde 7,

affording the corresponding chiral alcohol 8 with 86% ee.

Chapter 2

32

Figure 3. Huber’s first catalytic asymmetric route to (R)‐(+)‐Lasiodiplodin.

Recently, the group of Faber14 reported a chemenzymatic asymmetric route towards

(R)-(+)-lasiodiplodin (Figure 4). The stereogenic center was introduced by alkyl sulfatase

Pisa1-catalyzed deracemization reaction. Racemic Sulfate ester 16 was hydrolyzed with

inversion of the stereocenter using alkyl sulfatase Pisa1 to product 18 with >99% ee. The

remaining enantiomer 17 was hydrolyzed using p-TSA with retention of configuration to

give product 18 with 93% ee.

Chapter 2

33

Figure 4. Faber’s enzymatic route.

In order to develop a short catalytic asymmetric route with precise control over the

absolute configuration in this important class of compounds, a catalytic approach is

reported for the synthesis of (R)-(+)-lasiodiplodin methyl ether using highly

enantioselective copper-catalyzed asymmetric hetero allylic alkylation as the key step.15

2.4 Formal synthesis of (R)-(+)-Lasiodiplodin

2.4.1 First retrosynthetic analysis

Figure 5. First retrosynthesis of (R)‐(+)‐Lasiodiplodin.

In our retrosynthetic analysis (Figure 5), the macrocycle 22 was planned to be formed not

by macrolactonization, but by ring-closing metathesis to afford, after hydrogenation, the

C13–C14 bond. In this way, the starting material for this ring-closing reaction, 23, can be

prepared from allyl bromide 24 by copper-catalyzed asymmetric allylic alkylation

Chapter 2

34

recently developed in our group. Bromide 24 can be prepared from iodide 25.

2.4.2 Results and discussion The synthesis started with a Vilsmeier-Haack reaction16 of commercially available iodide

25 to afford aldehyde 26 in 64% yield (Figure 6). The initially attempted sp2-sp3 Suzuki

coupling using PdCl2 and 1,1′-bis(diphenylphosphino)ferrocene (dppf), water and Cs2CO3

at room temperature17 led to isomerization of the terminal alkene of compound 27.

Fortunately, a catalytic amount of AsPh3 significantly improved the outcome and afforded

compound 27 in 52% yield. This approach is reminiscent to the work of Bracher and

Schulte, who used a Pd(PPh3)4 catalyzed cross coupling between a related aryl triflate and

a 9-BBN alkyl borane obtained via hydroboration.11a Subsequent Pinnick oxidation18 of

aldehyde 27 gave acid 28 in 80% yield. The preparation of acid bromide 29 using oxalyl

bromide gave full conversion, however, the synthesis of allyl bromide 24 using acid

bromide 29 and acrolein gave a complex mixture of products.

Figure 6. Attempted synthesis of allyl bromide 24.

2.4.3 Second retrosynthetic analysis

Figure 7. Second retrosynthesis of (R)‐(+)‐Lasiodiplodin.

In our second retrosynthetic analysis (Figure 7), starting material 23 for the ring-closing

reaction can be prepared from allylic alcohol 31, containing the stereogenic center, and

tetrasubstituted benzene 30 (as its acyl fluoride, vide infra). Alcohol 31 is accessible in

Chapter 2

35

high yield and enantioselectivity by the above mentioned copper-catalyzed asymmetric

hetero allylic alkylation reaction recently developed in our group (Figure 8).

Figure 8. Copper‐catalyzed asymmetric allylic alkylation.

2.4.4 Results and discussion

Figure 9. Synthesis of (R)‐(+)‐Lasiodiplodin.

The allylic alcohol 31 was formed by hydrolysis of ester 33 in turn obtained by catalytic

asymmetric allylic alkylation (Figure 8). Attempted esterification of acid 28 and alcohol

31 using carbodiimide-based reagents or the Yamaguchi method met with failure.

Fortunately, the method reported by Fürstner strongly improved the outcome.19 Switching

to acid fluoride 34 prepared by treatment of 28 with cyanuric fluoride,20 afforded

compound 23 in 90% yield. This was followed by alkene ring-closing metathesis21 using

Hoveyda-Grubbs 2nd generation catalyst (Grubbs’ first and second generation catalysts

gave only low yield) in refluxing toluene to afford a cis/trans mixture of alkene 35 in

80% yield (E/Z =1/2). A similar strategy was applied by the group of Fürstner for the

construction of the macrocycle.10b,11c,11d Hydrogenation22 of alkene 35 afforded the final

product 2223 in quant. yield and the optical rotation and spectroscopic data were in

agreement with the reported data.11d (R)-(+)-lasiodiplodin (1) and its de-O-methyl

congener 2 are readily prepared from 22 according to literature procedures, although with

low yields.10a,10c,11a

Chapter 2

36

2.5 Conclusion

In summary, we have completed the formal total synthesis of (R)-(+)-lasiodiplodin using

catalytic asymmetric allylic substitution, sp3-sp2 Suzuki coupling and RCM as key steps.

Asymmetric allylic alkylation was the step in the synthesis used to obtain the chiral

allylic alcohol building block. The new synthetic route is currently explored in the

preparation of other biologically active resorcylic acid lactones.

2.6 Experimental section

Starting materials were purchased from Aldrich, Alpha Aesar or Acros and used as

received unless stated otherwise. All solvents were reagent grade and, if necessary, dried

and distilled prior to use. Column chromatography was performed on silica gel

(SiliaFlash®60, 230-400 mesh). TLC was performed on silica gel 60/Kieselguhr F254.

1H and 13C NMR spectra were recorded on a Varian VXR300 (299.97 MHz for 1H, 75.48

MHz for 13C) or a Varian AMX400 (399.93 MHz for 1H, 100.59 MHz for 13C)

spectrometer in CDCl3 unless stated otherwise. Chemical shifts are reported in values

(ppm) relative to the residual solvent peak (CHCl3, 1H = 7.24, 13C = 77.0). Carbon

assignments are based on 13C and APT 13C experiments. Splitting patterns are indicated as

follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

High resolution mass spectra (HRMS) were recorded on an AEI-MS-902 and a FTMS

orbitrap (Thermo Fisher Scientific) mass spectrometer. Optical rotations were measured

on a Schmidt+ Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in

g/100 mL).

2-Iodo-4,6-dimethoxybenzaldehyde (26):16 To a stirred solution of iodide 25 (4.70 g,

17.8 mol) in 30 mL of DMF was carefully added POCl3 (7.25 g, 47.3

mol) at 0 oC. The resulting mixture was heated to 100 oC for 4 h, then

poured onto ice and left overnight. The precipitate was filtered and

washed with water. The aqueous solution was extracted with DCM (3x 30 mL). The

combined organic layers were dried over Na2SO4, filtered, concentrated and purified by

flash chromatography (eluent pentane/ether = 10/1) to give 26 as a yellow solid (3.33 g,

11.4 mol, 64%). The NMR data are in agreement with these reported.16 1H NMR (400

MHz, CDCl3) δ 10.14 (s, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 3.89 (s,

3H), 3.86 (s, 3H).

O

O I

O

Chapter 2

37

6-(Hept-6-en-1-yl)-2,4-dimethoxybenzaldehyde (27): To a stirred solution of

7-bromohept-1-ene (651 mg, 0.52 mL, 3.68 mmol) in THF

(15 mL) was added rapidly t-BuLi (4.60 mL, 1.6 M in

heptane, 7.36 mmol) at –78 °C. After 30 min,

9-methoxy-9-borabicyclo[3.3.1]nonane (9.20 mL, 1 M in hexanes, 9.20 mmol) was added.

The resulting solution was stirred for 10 min at –78 °C and then allowed to warm to room

temperature for 1.5 h. Cs2CO3 (4.80 g, 14.7 mol)) was added, followed by the addition of

iodide 26 (1.07 g, 3.68 mmol) in 20 mL of DMF. PdCl2-(dppf) (150 mg, 0.184 mmol,

dppf = 1,1′-bis(diphenylphosphino)ferrocene) was added, followed by water (1.59 mL)

and AsPh3 (169 mg, 0.55 mmol). The resulting solution was stirred for 16 h at room

temperature. Et2O was added, and the organic solution was washed with H2O. The

aqueous layer was extracted with Et2O (3x 30 mL), and the combined organic layers were

dried over Na2SO4, filtered, concentrated and purified by flash chromatography (eluent

pentane/ether = 10/1) to give 27 as a colorless oil with traces of 9-BBN residues visible in

the 13C-NMR spectrum (500 mg, 1.91 mmol, 52%) that were removed in the next step. 1H

NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 6.31 (s, 2H), 5.80 (ddt, J = 16.9, 10.1, 6.7 Hz,

1H), 4.99 – 4.89 (m, 1H), 4.93 – 4.89 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.95 – 2.92 (m,

2H), 2.41 – 2.38 (m, 2H), 1.89 – 1.83 (m, 2H), 1.59 – 1.50 (m, 2H), 1.41– 1.38 (m 2H). 13C NMR (100 MHz, CDCl3) δ 190.4, 165.6, 164.7, 149.8, 139.4, 117.0, 114.4, 108.2,

95.9, 56.0, 55.6, 34.8, 34.0, 31.3, 29.5, 29.0. HRMS (ESI+): m/z [M+H]+ calc. for

C16H23O3: 263.1642, found: 263.1643.

6-(Hept-6-en-1-yl)-2,4-dimethoxybenzoic acid (28): To a stirred solution of aldehyde

27 (420 mg, 1.61 mmol) in 30 mL t-BuOH/H2O (5/1) was

added NaH2PO4 (0.340 g, 2.87 mol), NaClO2 (0.690 g,

7.64 mol) and 2-methyl-2-butene (806 mg, 1.21 mL, 11.5

mmol). The resulting solution was stirred for 4 h and the

solvent was removed. The resulting mixture was extracted with DCM (3x 30 mL). The


flash chromatography (eluent heptane/EtOAc =1/2) to give 28 as a brown oil (360 mg,

1.29 mmol, 80%). 1H NMR (400 MHz, CDCl3) δ 10.03 (br, 1H), 6.38 (d, J = 2.2 Hz, 1H),

6.35 (d, J = 2.2 Hz, 1H), 5.79 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.01– 4.90 (m, 2H), 3.87

(s, 3H), 3.82 (s, 3H), 2.79 – 2.75 (m, 2H), 2.06 – 2.01 (m, 2H), 1.66 – 1,58 (m, 2H), 1.44

– 1.36 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 171.6, 162.2, 159.1, 146.1, 139.3, 114.5,

O

O

O

O

O

O

OH

Chapter 2

38

114.0, 107.3, 96.6, 56.4, 55.6, 34.8, 33.9, 31.5, 29.3, 28.9. HRMS (ESI+): m/z [M+H]+

calc. for C16H23O4: 279.1591, found: 279.1594.

6-(Hept-6-en-1-yl)-2,4-dimethoxybenzoyl fluoride (34): To a stirred solution of acid 28

(100 mg, 0.36 mmol) in 4 mL of DCM was added

cyanuric fluoride (72.9 mg, 46.0 μL, 0.54 mmol) and

pyridine (85.4 mg, 87.0 μL, 1.08 mmol) at 0 oC. The

resulting mixture was stirred for 4 h and then quenched

with water. The aqueous mixture was extracted with DCM (3x 30 mL). The combined

organic layers were dried over Na2SO4, filtered, concentrated and purified by flash

chromatography (eluent heptane/EtOAc =1/1) to give 34 as a colorless oil (77 mg, 0.27

mmol, 76%). 1H NMR (400 MHz, CDCl3) δ 6.37 (d, J = 2.2 Hz, 1H), 6.34 (d, J = 2.2 Hz,

1H), 5.80 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.02 – 4.95 (m, 1H), 4.95 – 4.89 (m, 1H), 3.85

(s, 3H) , 3.84 (s, 3H), 2.76 – 2.64 (m, 2H), 2.09 – 1.98 (m, 2H), 1.66 – 1.51 (m, 2H), 1.46

– 1.29 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 163.8, 161.2 (d, J = 2 Hz), 159.1, 155.6,

147.7 (d, J = 3 Hz), 139.2, 114.5, 107.2, 96.5, 56.2, 55.7, 34.8, 33.9, 31.6, 29.2, 28.9; 19F

NMR (376 MHz, CDCl3) δ 51.49. HRMS (ESI+): m/z [M]+ calc. for C16H21FO3: 303.1367,

found: 303.1364.

(-)-(R)-But-3-en-2-yl-6-(hept-6-en-1-yl)-2,4-dimethoxybenzoate (23): To a stirred

aqueous solution (4 mL) of ester 33 (138 mg, 0.78 mmol,

97% ee) was added KOH (439 mg, 7.8 mmol). The

resulting mixture was stirred overnight, extracted with

Et2O (3x 5 mL), and the combined organic layers were

dried over Na2SO4, and filtered. The crude alcohol 31 was used for the next step without

complete removal of the solvent in order to avoid loss due to evaporation of the volatile

alcohol.

1H NMR (400 MHz, CDCl3) δ 5.92 (ddd, J = 17.2, 10.4, 5.8 Hz, 1H), 5.24 – 5.19 (m, 1H),

5.12 – 4.97 (m, 1H), 4.40 – 4.17 (m, 1H), 1.57 (br, 1H), 1.28 (d, J = 6.4 Hz, 3H).

To a stirred solution of alcohol 31 (0.78 mmol) in 2 mL of THF was added NaHMDS

(0.78 mL, 0.78 mmol, 1 M in THF) at 0 oC and the solution was stirred for 10 min. A

THF solution (2 mL) of acid fluoride 34 (30.0 mg, 0.10 mmol) was added slowly; the

mixture was warmed to room temperature and stirred overnight. The reaction was

quenched with aq. sat. NH4Cl and extracted with Et2O (3x 10 mL), and the combined


O

O

O

F

O

O

O

O

Chapter 2

39

chromatography (eluent pentane/ether =20/1) to give 23 as a colorless oil (30.2 mg, 0.09

mmol, 90%).

1H NMR (400 MHz, CDCl3) δ 6.31 (s, 2H), 5.92 (ddd, J = 16.7, 10.6, 5.9 Hz, 1H), 5.85 –

5.72 (m, 1H), 5.63 – 5.59 (m, 1H), 5.36 (d, J = 17.3 Hz, 1H), 5.18 (d, J = 10.5 Hz, 1H),

5.04 – 4.88 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 2.58 – 2.53 (m, 2H), 2.04 – 2.02 (m, 2H),

1.63 – 1.56 (m, 2H), 1.42 (d, J = 6.5 Hz, 3H), 1.48 – 1.18 (m, 4H). 13C NMR (100 MHz,

CDCl3) δ 162.8, 156.5, 153.2, 137.9, 134.2, 132.9, 111.9, 111.3, 109.5, 101.0, 91.5, 66.9,

51.0, 50.6, 29.0, 28.9, 26.4, 24.3, 24.0, 15.2. HRMS (ESI+): m/z [M+Na]+ calc. for

C20H28NaO4: 355.1880, found: 355.1862. [α]D= –7.4 (c= 1.1, CHCl3).

(+)-(R)-12,14-Dimethoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]oxacycl

ododecin-1-one (22): To a stirred solution of compound 23 (13.0 mg, 0.04 mmol) in

toluene (30 mL) was added Hoveyda-Grubbs 2nd generation

catalyst ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)

dichloro(o-isopropoxyphenylmethylene)ruthenium, 1.30 mg, 2.00

mol, 5 mol%). The resulting solution was heated to reflux for 10

min under N2. The solvent was removed and the product was

purified by flash chromatography (eluent pentane/ether) to give 35 as a green oil (9.50

mg, 32.0 mol, 80%, E/Z =1/2) which was difficult to purify, so they were used

immediately for the next step.

To a stirred solution of compound 35 (9.50 mg, 0.03 mmol) in 2 mL of EtOAc was added

Pd/C (10.0 mg) and the resulting solution was treated with 1 atm of H2. The mixture was

stirred overnight and the solvent was removed, purified by flash chromatography (eluent

pentane/ether =10/1) to give 22 as a colorless oil (9.6 mg, 0.03 mmol, 100%). The NMR

data are in agreement with those reported previously.

1H NMR (400 MHz, CDCl3) δ 6.30 (d, J = 2.2 Hz, 1H), 6.32 (d, J = 2.2 Hz, 1H), 5.31 –

5.25 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 2.77 – 2.67 (m, 1H), 2.58 – 2.49 (m, 1H), 1.98 –

1.88 (m, 1H), 1.74 – 1.61 (m, 4H), 1.36 – 1.60(m, 5H), 1.32 (d, J = 6.5 Hz, 3H), 1.28

–1.24 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 168.5, 161.1, 157.7, 142.7, 118.9, 105.8,

96.3, 72.0, 55.9, 55.3, 32.3, 30.6, 30.1, 26.5, 25.4, 24.2, 21.2, 19.5. HRMS (ESI+): m/z

[M+H]+ calc. for C18H27O4: 307.1904, found: 307.1897. [α]D= +10.5 (c= 0. 1, CHCl3)

[Lit11d = +8.7 (c= 1.63, CHCl3), Lit 11b= +9 (c= 1.0, CHCl3), Lit12 = +4.2 (c= 0.18,

CHCl3)].

OMe

MeO

O

O

Chapter 2

40

2.7 Reference and notes

1. (a) S. A. Hitchcock, G. Pattenden, J. Chem. Soc. Perkin Trans. 1, 1992, 1323–1328. (b) E.

Keinan, S. Sinha, A. Sinhabachi, J. Chem. Soc. Perkin Trans.1, 1991, 3333–3339. (c) K. C.

Nicolaou, N. Winssinger, J. Pastor, F. Murphy, Angew. Chem., 1998, 110, 2677; Angew. Chem.

Int. Ed., 1998, 37, 2534–2537.(d) D. Taub, N. N. Girotra, R. D. Hoffsommer, C. H. Kuo, H. L.

Slates, S. Weber, N. L. Wendler, Tetrahedron, 1968, 24, 2443– 2461.

2. M. P. Baggelaar, Master Report, University of Groningen, 2012.

3. W. H. Utian, Br. Med. J., 1973, 1, 579–581.

4. V. Helwig, A. Mayer-Bartschmid, H. Mueller, G. Greif, G. Kleymann, W. Zitzmann, H. V.

Tichy, M. Stadler, J. Nat. Prod.,2003, 66, 829.

5. M. Isaka, C. Suyarnsestakorn, M. Tanticharoen, P. Kongsaeree, Y. Thebtaranonth, J. Org.

Chem., 2002, 67, 1561.

6. (a) D. C. Aldridge, S. Galt, D. Giles, B. Turner, J. Chem. Soc. C., 1971, 1623. (b) R. C.

Cambie, A. R. Lal, P. S. Rutledge, P. D. Woodgate, Phytochemistry, 1991, 30, 287. (c) K.-H.

Lee, N. Hayashi, M. Okano, I. H. Hall, R.-Y. Wu, A. T. McPhail, Phytochemistry, 1982, 21,

1119.

7. Y. Xin-Sheng, Y. Ebizuka, H. Noguchi, F. Kiuchi, Y. Litaka, U. Sankawa, H. Seto, Tetrahedron

Lett., 1983, 2407.

8. P. M. Dewick, Medicinal Natural Products: a biosynthetic approach, Wiley, 2009.

9. (a) T. Kashima, K. Takahashi, H. Matsuura, K. Nabeta, Biosci. Biotechnol. Biochem., 2009, 73,

1118. (b) T. Kashima, K. Takahashi, H. Matsuura, K. Nabeta, Biosci. Biotechnol. Biochem.,

2009, 73, 2522.

10. (a) S. J. Danishefsky, S. J. Etheredge, J. Org. Chem., 1979, 44, 4716–4717. (b) A. Fürstner, O.

R. Thiel, N. Kindler, B. Bartkowska, J. Org. Chem., 2000, 65, 7990–7995. (c) H. Gerlach, A.

Thalmann, Helv. Chim. Acta., 1977, 60, 2866– 2866. (d) T. Takahashi, K. Kasuga, J. Tsuji,

Tetrahedron Lett., 1978, 19, 4917–4920.

11. (a) F. Bracher, B. J. Schulte, J. Chem. Soc. Perkin Trans. 1, 1996, 2619–2622. (b) M. Braun,

U. Mahler, S. Houben, Liebigs Ann. Chem., 1990, 513–517. (c) A. Fürstner, N. Kindler,

Tetrahedron Lett., 1996, 37, 7005–7008. (d) A. Fürstner, G. Seidel, N. Kindler, Tetrahedron,

1999, 55, 8215–8230.

12. A. R. Solladié, M. C. Carreno, J. L. G. Ruano, Tetrahedron: Asymmetry, 1990, 1, 187–198.

13. G. B. Jones, R. S. Huber, Synlett., 1993, 367–368.

14. M. Fuchs, M. Toesch, M. Schober, C. Wuensch, K. Faber, Eur. J. Org. Chem., 2013, 356–361.

15. K. Geurts, S. P. Fletcher, B. L. Feringa, J. Am. Chem. Soc., 2006, 128, 15572–15573.

16. H. Abe, K. Nishioka, S. Takeda, M. Arai, Y. Takeuchi, T. Harayama, Tetrahedron Lett., 2005,

46, 3197.

Chapter 2

41

17. S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem. Int. Ed., 2001, 40, 4544.

18. L. S. -M. Wong, M. S. Sherburn, Org. Lett., 2003, 5, 3603.

19. A. Fürstner, M. Bindl, L. Jean, Angew. Chem. Int. Ed., 2007, 46, 9275.

20. G. A. Olah, M. Nojima, I. Kerekes, Synthesis, 1973, 487.

21. M. T. Crimmins, E. A. Tabet, J. Am. Chem. Soc., 2000, 122, 5473.

22. K. J. Quinn, J. M. Curto, K. P. McGrath, N. A. Biddick, Tetrahedron Lett., 2009, 50, 7121.

23. The final product 22 seems unstable upon storing at room temperature.

Chapter 2

42

Chapter 3

43

Chapter 3

A Concise Asymmetric Synthesis of (–)‐Rasfonin

In this chapter the catalytic asymmetric formal synthesis of (–)-Rasfonin is described.

CuBr/JosiPhos catalyzed iterative asymmetric conjugate addition of MeMgBr and

Feringa’s butenolide are the key strategic elements in this synthesis.

Parts of this chapter have been published: Y. Huang, A. J. Minnaard, B. L. Feringa, Org.

Biomol. Chem., 2012, 10, 29–31.

Chapter 3

44

3.1 Introduction

Natural products containing α-pyranones (δ-lactones) show a variety of interesting

biological properties (Figure 1). For example, PD 113.271, which was isolated by the

group of Tunac in 1983, exhibits promising cytotoxic activities.1 EBC-23, which was

found in the fruit of Cinnamomum laubatii, shows excellent in vitro anticancer activities.2

(+)-Goniotriol, which belongs to the styryllactones, shows significant cytotoxicity against

several human tumor cell lines.3 As a prime example, rasfonin 1,4 isolated from the

fungus Trichurus terrophilus and the fermented mycelium of Taleromyces species

3565-A1, has been reported as an active apoptosis inducer in ras-dependent cells. In

connection with this finding, significant proliferation suppression of mouse splenic

lymphocytes stimulated with mitogens, concanavalin A and lipopolysaccharide, was

reported.

OO

O

OOH

OHRasfonin 1

OO

OH

O

HO

OH

PD 113.271

OO

HO

HO

Ph

HO

H

(+)-Goniotriol

O

O OOHOH

OH

H12

EBC-23

OH

PO

OHO-Na+

Figure 1. Natural products containing α‐pyranones.

2.2 Previous total syntheses of rasfonin

Due to the potential use of (–)-1 in the development of cancer chemotherapeutics, a

versatile synthetic route to rasfonin is required to establish which parts of the molecule

are important for activity, and to pin down its target protein(s). The first total synthesis of

(–)-1, reported by Ishibashi and co-workers in 2003, aimed at structure elucidation and

absolute configuration determination.5 A second synthesis, reported by the group of

Boeckman in 2006,6 was based on the use of camphor lactam chiral auxiliaries (2a, 2b,

Chapter 3

45

2c) in order to allow the synthesis of different stereoisomers and cationic chiral

oxazaborolidine catalyst 3 in the key assembly of butenolide 4 via an asymmetric

vinylogous Mukaiyama aldol addition (Figure 2).

Figure 2. Boeckman’s total synthesis of Rasfonin 1.

Recently, the group of Nanda7 reported a chemoenzymatic asymmetric synthesis of

rasfonin 1. Enantioselective enzymatic desymmetrization (EED) to form ester 5 and 6

and Gluconobacter oxydans mediated oxidative kinetic resolution (OKR) to prepare 7

have been applied for the introduction of 3 stereocenters (Figure 3).

Chapter 3

46

Figure 3. Nabda’s methodology to the synthesis of rasfonin 1.

As no follow-up appeared in chemical biology, we felt that a concise synthesis of 1,

taking advantage of highly efficient and selective catalytic methods and making this

compound and analogs more readily available could greatly stimulate biological studies.

Herein, we report the asymmetric synthesis of (–)-1 in a highly efficient and selective

manner.

2.3 Total synthesis of Rasfonin

2.3.1 Retrosynthetic analysis

OO

O

OOH

OH

OO

OH

HO

O

OTBS

OTBS

1

8

9

TBDPSOS

O

OO

OMenthyl

10

11

Figure 4. Retrosynthesis of Rasfonin 1.

In our retrosynthetic analysis, (–)-rasfonin 1 was disconnected into upper half 8 and

lower half 9. The former was planned to be obtained from 10, in turn prepared via our

iterative catalytic asymmetric conjugate addition protocol to deoxypropionates,8 in

combination with a stereospecific Achmatowicz rearrangement. The lower part, 9,

should in principle be accessable starting from readily available enantiopure

Feringa’s menthyl butenolide 11.9

Chapter 3

47

2.3.2 Synthesis of upper half of Rasfonin

Figure 5. Synthesis of the upper half of Rasfonin 1.

The synthesis of the upper half of Rasfonin 1 started with the preparation of

syn-1,3-dimethyl thioester 10 in an excellent 57% overall yield starting from ethylene

glycol 12 by CuBr/JosiPhos catalyzed iterative asymmetric conjugate addition of

MeMgBr.10 Reduction of 10 with DIBAL afforded the corresponding aldehyde which was

used immediately to form the terminal alkyne 13 by addition of lithiated

trimethylsilyldiazomethane involving a Colvin rearrangement (Figure 6).11 Vinyl iodide

14 was subsequently prepared by Zr-catalyzed methylalumination,12 followed by Negishi

cross coupling11 with ZnMe2 to afford alkene 15, which after deprotection with TBAF

provided alcohol 16 in 87% yield. Ley oxidation13 of 16 afforded the corresponding

aldehyde which was treated with 2-furyl lithium to give the corresponding furyl alcohol

in 88% yield (syn/anti= 2/1). Subsequent Ley oxidation of this mixture gave ketone 17 in

98% yield which was in turn treated with (S)-CBS reagent and borane14 to afford furyl

alcohol 18 in an excellent 94% yield and a syn/anti ratio >98:2. Stereospecific

Achmatowicz rearrangement (Figure 7)15 of 18 with vanadyl acetylacetonate and

Chapter 3

48

tert-butylhydroperoxide afforded the hemi-acetal in 69% yield which was subsequently

oxidized by Jones’ reagent16 to the corresponding ketolactone. Finally, Luche reduction17

gave the upper half 8 as the only diastereomer.

Figure 6. Mechanism of the Colvin rearrangement.

Figure 7. Mechanism of the Achmatowicz rearrangement.

2.3.3 Synthesis of lower half of Rasfonin 1

Figure 8. Preparation of vinyl iodide 21.

The synthesis of lower half of Rasfonin 1 started with the preparation of vinyl iodide 20.

Zr-catalyzed methylalumination (Figure 8) of alcohol 19 afforded vinyl iodide 20 in only

53% yield, which was followed by protection to form the desired fragment 21 in high

yield. Due to the low yield of the first step, the reverse synthesis sequence was tried

(Figure 9). Protection using p-MeOBnCl afforded 22 in good yield, however, the

subsequent Zr-catalyzed methylalumination of 22 gave deprotected product 20.

Chapter 3

49

Figure 9. Preparation vinyl iodide 21.

Fortunately, stannyl cupration18 solved the problem (Figure 10). By mixing CuCN,

n-Bu3SnH and n-butyl lithium, the complex (Bu3Sn)2CuCNLi2 formed, followed by

syn-addition on the alkyne to give vinyltin cuprate 23. Coupling with methyl iodide

afforded vinyltin 24 followed by iodinolysis gave the desired compound 21 in overall

82% yield in one pot!

Figure 10. Stannyl cupration of alkyne 22.

Initial conjugate addition (Table 1) of vinyl iodide 21 on Feringa’s Butenolide 11 using

nBuLi and CuI gave a complex mixture of products; both starting materials seemed to

decompose during the reaction. Similar results were obtained by changing Li-source

(from nBuLi to tBuLi), using additives (nBu3P, TMSCl and BF3•Et2O) or even applying

CuCN.19

Chapter 3

50

Table 1. Conjugate addition of vinyl iodide 21 on Feringa’s butenolide 11.

Entry Condition Yield

1 1. n‐BuLi, ‐78 oC; 2. CuI, ‐78 oC ‐‐

2 1. t‐BuLi, ‐78 oC; 2. CuI, ‐78 oC ‐‐

3 1. t‐BuLi, ‐78 oC; 2. CuI, n‐Bu3P, ‐78 oC ‐‐

4 1. t‐BuLi, ‐78 oC; 2. CuBr•SMe2, TMSCl, ‐78 oC ‐‐

5 1. t‐BuLi, ‐78 oC; 2. CuI, BF3•Et2O, ‐78 oC ‐‐

6 1. t‐BuLi, ‐78 oC; 2. CuCN, ‐78 oC ‐‐

The new route towards the synthesis of lower half 9 started with Michael addition (Figure

11) of lithium bis(phenylthio)methane to butenolide 11 to provide trans-26 as the single

diastereomer in 86% yield. Full reduction of 26 by LiAlH4 afforded diol 27 in 90% yield

which after protection provided 28 in 96% yield. Unmasking dithiane 28 by HgCl2 and

HgO in a mixture of acetonitrile and water went smoothly and afforded the free aldehyde

29 in 85% yield. Initial preparation of the internal alkyne 32 by Corey-Fuchs reaction20

gave only 40% overall yield which was due to the low yield of the first step to the

formation of bis-bromide 31. The Bestmann-Ohira reaction21 gave similar results as

Corey-Fuchs. Fortunately, Colvin rearrangement improved the yield by 20%.

Chapter 3

51

Figure 11. New route towards lower half of Rasfonin 1.

Initial transformation of the internal alkyne 32 to vinyl iodide 34 using stannyl cupration

gave no conversion at all. The application of Schwartz’s hydrozirconation22 afforded a

complex mixture of products at gram scale. However, hydrostannation23 improved the

result. The first attempt (Table 2, entry 1) using 5 mol% Pd(PPh3)2Cl2 with nBu3SnH in

pentane gave 33 in 33% yield as the only regioisomer after iodinolysis. Switching to a

polar solvent (THF) didn’t improve the yield a lot. Interestingly it was observed that 1

equiv. of catalyst gave a similar yield as 5 mol% (entry 3), the catalyst seems deactivated

after 5 min. Reformation the catalyst every 5 min also didn’t help. Fortunately, the

method proposed by Semmelhack and Hooley24 strongly improved the outcome.

Switching to catalytic Pd(OAc)2 and tricyclohexyl phosphine, with hexane as the solvent,

led to complete conversion and 80% isolated yield in 20 min!

Chapter 3

52

Table 2. Preparation of vinyl iodide 34 from internal alkyne 32.

Entry Conditions Yield (58)

1 Pd(PPh3)2Cl2 (5 mol%), nBu3SnH, n‐pentane 33%

2 Pd(PPh3)2Cl2 (5 mol%), nBu3SnH, THF 41%

3 Pd(PPh3)2Cl2 (1 equiv.), nBu3SnH, n‐pentane 40%

4 Pd(OAc)2(5 mol%), PCy3, nBu3SnH, n‐hexane 80%

Stille coupling of acid 3525 and 34 provided the lower half 9 in 87% yield. The coupling

of the upper half 8 with the lower half 9 of (–)-rasfonin was achieved by Yamaguchi

esterification26 in 80% yield. Desilylation initially was not satisfactory as treatment with

camphorsulfonic acid gave only 40% yield. Fortunately, switching to aq. HF in

acetonitrile27 resulted in quantitative formation of (–)-rasfonin 1.

Figure 12. Completion of the synthesis of the lower half and coupling with the upper

half.

Chapter 3

53

2.4 Conclusion

In conclusion, a very efficient total synthesis of the apoptosis inducer (–)-rasfonin has been

developed. This synthetic route took 21 linear steps with 10.8% overall yield (16 linear

steps with 12.7% overall yield for Boeckman’s route, however, it contains a recycling

sequence). CuBr/JosiPhos catalyzed iterative asymmetric conjugate addition of MeMgBr

has been employed to install the stereogenic centers in the upper half side chain with

excellent yield and stereoselectivity. The hydroxy-lactone core could be prepared by a

subsequent stereospecific hydroxy-directed Achmatowicz rearrangement followed by an

oxidation-reduction sequence. The synthesis of the lower half 8 makes use of the perfect

transfer of chirality in the conjugate addition to butenolide 11 followed by selective

construction of the E,E-diene-ester part. The availability of an effective route to rasfonin

now allows to study its role in inhibiting the Ras signalling pathway, in addition, it

provides access to functional analogs and might lead to the identification of its target

protein.


Starting materials were purchased from Aldrich, Alfa Aesar or Acros and used as


and distilled prior to use. Column chromatography was performed on silica gel (Aldrich

60, 230-400 mesh) or on aluminium oxide (Merck, aluminium oxide 90 neutral activated).

TLC was performed on silica gel 60/Kieselguhr F254.



spectrometer in CDCl3 unless stated otherwise. Chemical shifts are reported in δ values


assignments are based on 13C and APT 13C experiments. Splitting patterns are indicated

as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

High resolution mass spectra (HRMS) were recorded on an AEI-MS-902 and FTMS



g/100 mL). Enantiomeric excess was determined by HPLC (Chiralcel OB, 250*4.6, 10

μm), (Chiralcel OD, 250*4.6, 10 μm).

Chapter 3

54

(–)-tert-Butyl((2S,4R)-2,4-dimethylhept-6-ynyloxy)diphenylsilane (13): To a stirred

mixture of 108 (1.98 g, 4.52 mmol) in dry DCM (100 mL)

was added DIBALH (5.89 mL, 5.89 mmol, 1.0 M solution in

DCM) at –65 °C under nitrogen. Stirring was continued until

TLC showed complete conversion (2-3 h). The reaction mixture was quenched with 60

mL saturated aqueous Rochelle salt (potassium sodium tartrate) and stirred for 30 min.

The phases were separated and the aqueous layer was extracted with DCM (3 x 50 mL).

The combined organic phases were dried over Na2SO4 and concentrated under reduced

pressure to yield crude aldehyde which was purified by flash chromatography (eluent

pentane/ether) to give the desired aldehyde used in the next step without complete

removal of the eluent.

To a THF (45 mL) solution of trimethylsilyldiazomethane (4.53 mL, 9.06 mmol, 2.0 M

solution in hexanes) was added n-BuLi (3.26 mL, 8.16 mmol, 2.5 M solution in hexanes)

at –78 ºC. After being stirred for 30 min, above aldehyde, dissolved in 20 mL of THF,

was added. The mixture was stirred for 0.5 h at –78 ºC and then warmed to room

temperature overnight. The mixture was quenched with saturated aqueous NH4Cl (20 mL)

and extracted with Et2O (3 x 20 mL). The combined organic layers were dried over

Na2SO4, filtered, concentrated and purified by flash chromatography (eluent

pentane/ether) to give 13 as a colorless oil (1.46 g, 85%): 1H NMR (400 MHz, CDCl3) δ

7.69- 7.67 (m, 4H), 7.41- 7.38 (m, 6H), 3.52 (dd, J= 5.4, 9.8 Hz, 1H), 3.43 (dd, J= 6.3,

9.8 Hz, 1H), 2.19- 2.13 (m, 1H), 2.04- 1.98 (m, 1H), 1.93 (t, J= 2.7 Hz, 2H), 1.77- 1.69

(m, 2H), 1.53 (dd, J= 6.6, 13.7 Hz, 1H), 1.06 (s, 9H), 0.97 (d, J= 6.7 Hz, 3H), 0.94 (d, J=

6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.9, 134.3, 129.7, 127.8, 83.4, 69.4, 69.0,

40.1, 33.4, 29.9, 27.1, 25.8, 20.3, 19.6, 17.7; HRMS (APCI+) calculated for C25H35OSi:

379.2452, found: 379.2448; [α]D = –9.2 (c= 1.6, CHCl3).

(-)-tert-Butyl ((2S, 4R, E)-7-iodo-2, 4, 6-trimethyl hept-6-enyloxy) diphenyl silane

(14): H2O (28.6 μL, 1.59 mmol) was added to a solution of Me3Al (7.95 mL, 15.9 mmol)

and ZrCp2Cl2 (233 mg, 0.79 mmol) in DCM (20 mL) at

–78oC. The mixture was warmed to room temperature and

stirred for 30 min, then cooled to –78 oC again. Alkyne 13

(1.20 g, 3.18 mmol) in 12 mL DCM was added slowly to the mixture. After stirring for 3

h at room temperature, the reaction mixture was treated with a solution of I2 (1.61 g, 6.36

mmol) in THF (10 mL) at –78oC. After stirring for 30 min at –78oC, the reaction mixture

was warmed to room temperature, quenched with saturated aqueous Na2S2O3 and

extracted with Et2O (3 x 20 mL). The combined organic layers were dried over Na2SO4,

filtered, concentrated and purified by flash chromatography (eluent pentane/ether) to give

TBDPSO

TBDPSO I

Chapter 3

55

14 as a colorless oil (1.46 g, 88%): 1H NMR (400 MHz, CDCl3) δ 7.70- 7.66 (m, 4H),

7.46- 7.37 (m, 4H), 5.82 (s, 1H), 3.50 (dd, J= 5.3, 9.9 Hz, 1H), 3.43 (dd, J= 6.2, 9.8 Hz,

1H), 2.19 (dd, J= 4.7, 13.3 Hz, 1H), 1.90 (dd, J= 9.3, 13.2 Hz, 1H), 1.77 (d, J= 1.0 Hz,

3H), 1.75- 1.66 (m, 2H), 1.39- 1.30 (m, 2H), 1.07 (s, 9H), 0.94 (d, J= 6.7 Hz, 3H), 0.77

(d, J= 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.4, 135.9, 135.8, 134.2, 129.8,

127.8, 75.4, 68.9, 47.7, 41.3, 33.4, 28.7, 27.1, 24.0, 20.1, 19.6, 18.1; HRMS (APCI+)

calculated for C26H38OSi: 521.1731, found: 521.1721; [α]D = –8.7 (c= 6.2, CHCl3).

(–)-tert-Butyldiphenyl((2S,4R,E)-2,4,6-trimethyloct-6-enyloxy)silane (15): Me2Zn (2.3

mL, 2.67 mmol, 1.2 M in heptane) was added dropwise to

a THF solution (30 mL) of vinyl iodide 14 (1.17 g, 2.22

mmol) and Pd(PPh3)2Cl2 (79.0 mg, 0.112 mmol) at 0 ºC.

The reaction mixture was allowed to warm to room temperature slowly, protected from

light and stirred overnight. The reaction was quenched with water, diluted with ether and

subsequently extracted with ether (3 x 30 mL), The combined organic layers were dried

over Na2SO4, filtered, concentrated and purified by flash chromatography (eluent

pentane/ether) to give 15 as a colorless oil (0.854 g, 96%): 1H NMR (400 MHz, CDCl3) δ

7.69- 7.67 (m, 4H), 7.45- 7.35 (m, 6H), 5.16 (q, J= 7 Hz, 1H), 3.51 (dd, J= 5.1, 9.8 Hz,

1H), 3.42 (dd, J= 6.4, 9.8 Hz, 1H), 1.99 (d, J= 8.3 Hz, 1H), 1.80- 1.73 (m, 1H), 1.67-

1.61 (m, 2H), 1.57(d, J= 6.8 Hz, 3H), 1.53 (s, 3H), 1.38- 1.27 (m, 2H), 1.06 (s, 9H), 0.95

(d, J= 6.7 Hz, 3H), 0.75 (d, J= 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.9, 135.0,

134.4, 129.7, 127.8, 119.9, 69.1, 48.0, 41.4, 33.5, 28.4, 27.1, 20.3, 19.6, 18.2, 15.8, 13.6;

HRMS (APCI+) calculated for C27H41OSi: 409.2921, found: 409.2915; [α]D = –7.8 (c=

1.0, CHCl3).

(-)-(2S,4R,E)-2,4,6-Trimethyloct-6-en-1-ol (16): To a stirred mixture of 15 (0.856 g, 2.1

mmol) in THF (25 mL) was added TBAF (1.0 M solution in

THF, 6.29 mL, 6.29 mmol). The resulting solution was stirred

for 4 h, and then quenched with sat. aq. NH4Cl and extracted

with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered,

concentrated and purified by flash chromatography (eluent pentane/ether) to give 16 as a

colorless oil (0.436 g, 87%): 1H NMR (400 MHz, CDCl3) δ 5.17 (dd, J= 6.2, 12.6 Hz,

1H), 3.52 (dd, J= 5.1, 10.5 Hz, 1H), 3.37 (dd, J= 6.8, 10.5 Hz, 1H), 2.04- 1.97 (m, 1H),

1.77- 1.63 (m, 3H), 1.57 (d, J= 8.5 Hz, 3H), 1.55 (s, 3H), 1.53 (br, 1H), 1.33- 1.25 (m,

2H), 0.93 ( d, J= 6.7 Hz, 3H), 0.81 (d, J= 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ

134.8, 120.1, 68.5, 47.8, 41.2, 33.4, 28.3, 20.4, 17.7, 15.8, 13.6; HRMS (APCI+)

calculated for C11H23O: 171.1743, found: 171.1739; [α]D = –4.2 (c= 1.1, CHCl3).

TBDPSO

HO

Chapter 3

56

(+)-(2S,4R,E)-1-(Furan-2-yl)-2,4,6-trimethyloct-6-en-1-one (17): To a stirred solution

of alcohol 16 (311 mg, 1.83 mmol) in DCM (15 mL) were

added molecular sieves 4Å (1.0 g), NMO (648 mg, 5.48

mmol) and TPAP (44.0 mg, 128 μmol). The reaction mixture

was stirred at rt for 1 h, filtered through a silica pad, concentrated under reduced pressure

and purified by flash chromatography (eluent pentane/ ether) to afford the aldehyde as a

colourless oil (277 mg, 90% yield): 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J= 2.6 Hz,

1H), 5.18 (dd, J= 6.6, 13.2 Hz, 1H), 2.48- 2.41 (m, 1H), 1.96 (dd, J= 5.8, 13.0 Hz, 1H),

1.78- 1.62 (m, 4H), 1.57 (d, J= 6.7 Hz, 3H), 1.54 (d, J= 1.0 Hz, 3H), 1.08 (d, J= 5.5 Hz,

3H), 0.83 (d, J= 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.7, 134.2, 120.6, 47.9,

44.4, 38.3, 28.6, 19.9, 15.7, 14.5, 13.6.

To a stirred solution of distilled furan (194 mg, 2.85 mmol) in THF was added n-BuLi

(0.61 mL, 1.52 mmol) at –78 oC. The reaction mixture was stirred for 3 h, and then a

THF solution (3 mL) of above aldehyde (160 mg, 0.95 mmol) was added slowly. The

reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was

quenched with sat. aq. NH4Cl and extracted with ether (3 x 10 mL), The combined


chromatography (eluent pentane/ether) to give the alcohol as a brown oil (0.197 g, 88%).

To a stirred solution of above alcohol (166 mg, 0.702 mmol) in DCM (15 mL) were

added molecular sieves 4Å (0.6 g), NMO (249 mg, 2.11 mmol) and TPAP (12 mg, 35

μmol). The reaction mixture was stirred at rt for 1 h, filtered through a silica pad,

concentrated under reduced pressure and purified by flash chromatography (eluent

pentane/ ether) to afford 17 as a brown oil (161 mg, 98% yield): 1H NMR (400 MHz,

CDCl3) δ 7.58 (s, 1H), 7.18 (d, J= 3.5 Hz, 1H), 6.52 (dd, J= 1.7, 3.5 Hz, 1H), 5.16 (dd,

J= 6.6, 13.3 Hz, 1H), 3.41- 3.32 (m, 1H), 1.98 (dd, J= 6.1, 13.1 Hz, 1H), 1.85 (ddd, J=

5.4, 8.8, 14.1 Hz, 1H), 1.72 (dd, J= 8.2, 13.1 Hz, 1H), 1.64- 1.48 (m, 1H), 1.55(d, J= 6.6

Hz, 3H), 1.49 (s, 3H), 1.17 (d, J= 6.9 Hz, 3H), 1.13- 1.08 (m, 1H), 0.79 (d, J= 6.6 Hz,

3H); 13C NMR (100 MHz, CDCl3) δ 193.8, 152.8, 146.6, 134.6, 120.2, 117.3, 112.3, 48.2,

40.9, 39.4, 28.8, 20.0, 18.4, 15.6, 13.6; HRMS (APCI+) calculated for C15H23O2:

235.1693, found: 235.1685; [α]D = +30.5 (c= 0.4, CHCl3).

(–)-(1R,2S,4R,E)-1-(Furan-2-yl)-2,4,6-trimethyloct-6-en-1-ol (18): To a stirred

solution of (S)-2-methyl-CBS- oxazaborolidine (43 μL , 0.043

mmol, 1.0 M solution in THF) in THF (0.6 mL) was added

borane-dimethylsufide complex (47 μL, 0.094 mmol, 2 M

O

O

O

OH

Chapter 3

57

solution in THF) followed by a solution of 17 (20 mg, 0.085 mmol) in THF (2 mL) at

0 °C and under N2. After 4 h, the mixture was quenched with sat. aq. NH4Cl and

extracted with ether (3 x 10 mL), The combined organic layers were dried over Na2SO4,

filtered, concentrated and purified by flash chromatography (eluent pentane/ether) to give

18 as a colorless oil (14.9 mg, 94%, syn/anti>98/2): 1H NMR (400 MHz, CDCl3) δ 7.37

(s, 1H), 6.33 (dd, J= 1.8, 3.2 Hz, 1H), 6.22 (dd, J= 0.6, 3.2 Hz, 1H), 5.15 (q, J= 7 Hz,

1H), 4.51 (d, J= 5.6 Hz, 1H), 2.10- 1.99 (m, 2H), 1.57 (d, J= 6.9 Hz, 3H), 1.54 (s, 3H),

1.33- 1.21 (m, 4H), 0.97 (d, J= 6.8 Hz, 3H), 0.79 (d, J= 6.1 Hz, 3H); 13C NMR (100 MHz,

CDCl3) δ 156.6, 141.8, 134.8, 120.1, 110.3, 106.5, 72.3, 47.4, 41.0, 35.8, 28.4, 20.5, 15.8,

15.6, 13.6; HRMS (ESI+) calculated for C15H25O2: 237.1854, found: 237.0879; [α]D =

–5.4 (c= 0.7, CHCl3).

(-)-(5R,6R)-6-((2S,4R,E)-4,6-Dimethyloct-6-en-2-yl)-5-hydroxy-5,6-dihydro-2H-pyra

n-2-one (8): To a stirred solution of furyl alcohol 18 (14.9 mg, 0.063 mmol) in DCM (1

mL) at 0 °C was added vanadyl acetylacetonate (0.8 mg,

0.003 mmol) followed by dropwise addition of

tert-butylhydroperoxide (0.012 mL, 0.063 mmol, 5.5 M in

decane). The solution was warmed to room temperature and stirred for 40 min. The

mixture was filtered through a silica pad, concentrated under reduced pressure and the

residue was purified by flash chromatography (eluent pentane/ ether) to afford the

hemiacetal as a colourless oil (7.3 mg, 69% yield).

Jones’ reagent (0.021 mL, 2.7 M) was added dropwise to an ice-cold solution of above

hemiacetal (7.0 mg, 0.029 mmol) in acetone (1 mL). The resulting mixture was stirred for

1 h at room temperature. The mixture was diluted with tert-butyl methyl ether (5 mL) and

washed with water; the organic phase was dried over Na2SO4, filtered, and the solvent

was evaporated to give the crude product keto-lactone which was used directly for the

next step: 1H NMR (400 MHz, CDCl3) δ 6.90 (d, J= 10.2 Hz, 1H), 6.78 (d, J= 10.2 Hz,

1H), 5.19 (dd, J= 6.6, 13.0 Hz, 1H), 4.90 (d, J= 2.4 Hz, 1H), 2.46- 2.37 (m, 1H), 2.02 (d,

J= 5.2, 12.4 Hz, 1H), 1.77- 1.53 (m, 4H), 1.58 (d, J= 7.0 Hz, 3H), 1.56 (s, 3H), 0.88 (d,

J= 6.8 Hz, 3H), 0.84 (d, J= 6.3 Hz, 3H).

To a solution of above keto-lactone in 1 mL of DCM was added NaBH4 (1.5 mg, 0.039

mmol) and CeCl3 (0.13 mL, 0.052 mmol, 0.4 M solution in MeOH) at –78oC. The

mixture was stirred for 0.5 h, warmed to room temperature and diluted with ether. The

mixture was quenched with 5 mL H2O, and extracted with ether (3 x 3 mL), The


flash chromatography (eluent pentane/ether) to give 8 as a colorless oil (6 mg, 80% based

on the keto-lactone): 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J= 6.1, 9.6 Hz, 1H), 6.10 (d,

OO

OH

Chapter 3

58

J= 9.6 Hz, 1H), 5.20 (dd, J= 6.0, 11.3 Hz, 1H), 4.22 (d, J= 4.1 Hz, 1H), 3.91 (dd, J= 2.3,

9.3 Hz, 1H), 2.27- 2.13 (m, 2H), 1.85- 1.73 (m, 1H), 1.58 (s, 6H), 1.45- 1.38 (m, 1H),

1.28- 1.22 (m, 1H), 1.14 (d, J= 6.5 Hz, 3H), 1.07- 0.98 (m, 1H), 0.84 (d, J= 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4, 144.6, 134.8, 123.2, 120.3, 85.6, 60.9, 46.6, 40.1,

31.5, 28.2, 21.2, 16.0, 15.8, 13.6; HRMS (ESI+) calculated for C15H24O3Na: 275.1617,

found: 275.1616; [α]D = –117.1 (c= 0.6, CHCl3).

(-)-(4R,5R)-4-(Bis(phenylthio)methyl)-5-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl

oxy)dihydrofuran-2(3H)-one (26): To a stirred solution of bis(phenylthio)methane (1.95

g, 8.4 mmol) in 50 mL THF was added n-BuLi (4.73 mL, 7.56

mmol) dropwise at –78oC. The reaction mixture was stirred for 0.5

h, followed by the addition of 11 in 20 mL THF. The mixture was

quenched with sat. aq. NH4Cl after TLC showed complete

conversion (2- 3 h). The mixture was extracted with ether (3 x 50 mL). The combined

organic layers were dried over Na2SO4, filtered, concentrated and the residue was

purified by flash chromatography (eluent pentane/ether) to give 26 as a white solid (1.71

g, 86% as the single diastereomer): 1H NMR (400 MHz, CDCl3) δ 7.50- 7.31 (m, 10H),

5.86 (s, 1H), 4.34 (d, J= 5.2 Hz, 1H), 3.52 (dt, J= 4.2, 10.7, 10.6 Hz, 1H), 2.87- 2.68 (m,

3H), 2.11- 1.98 (m, 2H), 1.68- 1.58 (m, 2H), 1.44- 1.29 (m, 1H), 1.23- 1.16 (m, 1H),

1.06- 0.81 (m, 3H), 0.93 (d, J= 6.5 Hz, 3H), 0.86 (d, J= 7.0 Hz, 3H), 0.77 (d, J= 6.9 Hz,

3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 133.9, 133.4, 133.3,133.3, 133.1, 129.5,

129.5, 128.9, 128.7, 102.4, 77.7, 61.3, 48.0, 46.7, 40.1, 34.5, 32.4, 31.6, 25.7, 23.3, 22.5,

21.1, 15.9; HRMS (APCI+) calculated for C21H29O3S: 361.1832, found: 361.1812; [α]D =

–83.5 (c= 1.3, CHCl3).

(+)-(R)-2-(Bis(phenylthio)methyl)butane-1,4-diol (27): To a stirred solution of 26 (1.51

g, 3.2 mmol) in 100 mL THF was added LiAlH4 (3.2 mL, 12.8 mmol, 4

M solution in diethylether) dropwise at 0 oC. The mixture was stirred

for an additional 0.5 h at 0 oC and then warmed to room temperature.

The mixture was quenched with 10 mL H2O after complete conversion

shown by TLC. The resulting mixture was subsequently filtered, and extracted with ether

(3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated

and the residue was purified by flash chromatography (eluent pentane/ether) to give 27 as

a white solid (0.856 g, 90%): 1H NMR (400 MHz, CDCl3) δ 7.45- 7.24 (m, 10H), 4.67 (d,

J= 3.5 Hz, 1H), 3.83 (t, J= 6.1 Hz, 2H), 3.78- 3.71 (m, 1H), 3.65- 3.58 (m, 1H), 3.22 (br,

1H), 2.92 (br, 1H), 2.23- 2.20 (m, 1H), 2.10- 2.07 (m, 1H), 1.82- 1.70 (m, 1H); 13C NMR

(100 MHz, CDCl3) δ 134.9, 134.8, 132.7, 132.5, 129.3, 128.0, 127.9, 64.6, 63.0, 61.6,

O

O

OMenthyl

PhS

SPh

OH

PhS

SPh

OH

Chapter 3

59

44.3, 32.5; HRMS (ESI+) calculated for C17H19O2S2: 319.0826, found: 319.0801; [α]D =

+24.5 (c= 0.2, CHCl3).

(+)-(R)-6-(Bis(phenylthio)methyl)-2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disil

adodecane (28): To a solution of 27 (0.752 g, 2.35 mmol) in anhydrous dichloromethane

(30 mL) was added imidazole (1.28 g, 18.8 mmol) followed by

tert-butyl-dimethylsilyl chloride (2.83 g, 18.8 mmol), and the

resulting white suspension was stirred at rt overnight. The reaction

mixture was quenched with 20 mL of water and extracted with ether

(3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated

and purified by flash chromatography (eluent pentane/ether) to give 28 as a colorless oil

(1.24 g, 96%): 1H NMR (400 MHz, CDCl3) δ 7.47- 7.20 (m, 10H), 5.05 (d, J= 2.7 Hz,

1H), 3.82- 3.79 (m, 2H), 3.66 (t, J= 6.1 Hz, 2H), 2.30- 2.27 (m, 1H), 2.11- 2.05 (m, 1H),

1.55- 1.44 (m, 1H), 0.87- 0.85 (m, 18H), 0.02- 0.00 (m, 12H); 13C NMR (100 MHz,

CDCl3) δ 136.2, 135.7, 131.8, 131.3, 129.0, 127.3, 127.0, 63.2, 62.0, 60.5, 43.3, 30.5,

26.1, 26.0, 18.5, 18.3, -5.2, -5.1; HRMS (APCI+) calculated for C23H44O2SSi2: 440.2595,

found: 440.2538; [α]D = +44.9 (c= 0.8, CHCl3).

(+)-(S)-6-Ethynyl-2, 2, 3, 3, 10, 10, 11,11-octamethyl-4,9-dioxa-3,10- disilado decane

(30): To a solution of thioacetal 28 (4.00 g, 7.29 mmol) in acetonitrile-water (4:1, 50 mL)

at room temperature was added HgCl2 (3.96 g, 14.6 mmol) and HgO

(3.16 g, 14.6 mmol), and the mixture was stirred for 3 h. Subsequent

fitration through Celite, followed by removal of the solvents under

reduced pressure. Purification by flash chromatography (eluent

pentane/ether) gave 29 as a colorless oil (2.14 g, 85%): 1H NMR (400 MHz, CDCl3) δ

9.74 (d, J= 1.7 Hz, 1H), 3.93- 3.82 (m, 2H), 3.73- 3.62 (m, 2H), 2.63- 2.57 (m, 1H), 2.01-

1.91 (m, 1H), 1.75- 1.65 (m, 1H), 0.87 (s, 18 H), 0.04 (s, 12H).

To a THF solution (45 mL) of trimethylsilyldiazomethane (10.93 mL, 21.86 mmol, 2.0 M

solution in hexanes) was added n-BuLi (12.8 mL, 20.4 mmol, 1.6 M solution in hexanes)

at –78 ºC. After being stirred for 30 min, a solution of 29 in THF (20 mL) was added. The

mixture was stirred for 0.5 h at –78 ºC and then warmed to room temperature overnight.

The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with

Et2O (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered,

concentrated and the product was purified by flash chromatography (eluent pentane/ether)

to give 30 as a colorless oil (1.42 g, 67%): 1H NMR (400 MHz, CDCl3) δ 3.80- 3.75 (m,

2H), 3.71 (dd, J= 5.7, 9.7 Hz, 1H), 3.58 (dd, J= 7.3, 9.7 Hz, 1H), 2.73- 2.63 (m, 1H), 2.03

(d, J= 2.4 Hz, 1H), 1.93- 1.82 (m, 1H), 1.61- 1.49 (m, 1H), 0.89 (s, 18H), 0.06 (s, 12H);

OTBS

PhS

SPh

OTBS

OTBS

OTBS

Chapter 3

60

13C NMR (100 MHz, CDCl3) δ 85.4, 70.1, 66.1, 60.9, 34.5, 31.6, 26.2, 26.1, 18.5, -5.1,

-5.1; HRMS (APCI+) calculated for C18H39O2Si2: 343.2483, found: 343.2472; [α]D =

+5.7 (c= 0.9, CHCl3).

(+)-(S)-2,2,3,3,10,10,11,11-Octamethyl-6-(prop-1-ynyl)-4,9-dioxa-3,10-disiladodecane

(32): Alkyne 30 (1.40 g, 4.09 mmol) was dissolved in dry THF (20 mL) and n-BuLi (5.1

mL, 8.17 mmol) was added at –78 oC under N2. After 10 min, MeI

(1.78 mL, 4.06 g, 28.6 mmol) was added. The resulting solution was

allowed to warm to 0 oC over 2 h, after which TLC showed complete

conversion. The reaction was quenched with saturated aqueous

NH4Cl (20 mL) and the mixture was extracted with Et2O (3 x 20 mL). The combined

organic layers were dried over Na2SO4, filtered, concentrated and the residue was

purified by flash chromatography (eluent pentane/ether) to give 32 as a colorless oil (1.33

g, 91%): 1H NMR (400 MHz, CDCl3) δ 3.83- 3.72 (m, 2H), 3.67 (dd, J= 5.6, 9.7 Hz, 1H),

3.50 (dd, J= 7.3, 14.1 Hz, 1H), 2.65- 2.52 (m, 1H), 1.93- 1.82 (m, 1H), 1.78 (d, J= 2.3 Hz,

3H), 1.53- 1.41 (m, 1H), 0.89 (s, 18H), 0.05 (s, 12H); 13C NMR (100 MHz, CDCl3) δ

80.4, 80.0, 66.6, 61.3, 34.9, 31.9, 26.2, 26.1, 18.6, 3.7, -5.1; HRMS (APCI+) calculated

for C19H40O2Si2Na: 379.2459, found: 379.2447; [α]D = +30.2 (c= 0.9, CHCl3).

(+)-(S,E)-6-(2-Iodoprop-1-enyl)-2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disilad

odecane (34): To an oven-dried, nitrogen-filled flask was added Pd(OAc)2 (15.71 mg,

0.07 mmol, 5 mol%) and tricyclohexylphosphine (39.26 mg, 0.14

mmol, 10 mol%) followed by freshly distilled hexane (25 mL) and

the resulting mixture was stirred for 20 min until the solids were

dissolved. Alkyne 32 (500 mg, 1.40 mmol) in hexane (10 mL) was added slowly,

followed by slow addition of neat Bu3SnH (1.56 mL, 5.61 mmol) over 5 min. The

reaction was finished after 20 min (TLC analysis) and the mixture was subsequently

transferred to a silica gel column and rapidly eluted with hexane, followed by

hexane/ether to provide 33 as a colorless oil (711 mg, 80%): 1H NMR (400 MHz, CDCl3)

δ 5.25 (dd, J= 1.1, 9.1 Hz, 1H), 3.66- 3.41 (m, 4H), 2.86- 2.73 (m, 1H), 1.92- 1.76 (m,

2H), 1.84 (s, 3H), 1.60- 1.43 (m, 7H), 1.36- 1.24 (m, 12H), 0.91- 0.83 (m, 9H), 0.88 (s,

18H), 0.03 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 142.5, 139.6, 66.9, 61.6, 37.4, 35.2,

29.4, 27.6, 26.2, 26.1, 19.9, 18.5, 13.9, 9.3, -5.1.

To a solution of 33 (622 mg, 0.96 mmol) in dichloromethane (20 mL) was added a

solution of I2 (487 mg, 1.92 mmol, 1.3 eq) in dichloromethane (15 mL) at –78 oC under

nitrogen. The resulting solution was stirred for 10 min at –78 oC and then allowed to

warm to room temperature. The solution was quenched with saturated aqueous Na2S2O3

OTBS

OTBS

OTBS

OTBS

I

Chapter 3

61

and extracted with Et2O (3 x 20 mL). The combined organic layers were dried over

Na2SO4, filtered, concentrated and the product was purified by flash chromatography

(eluent pentane/ether) to give 34 as a colorless oil (348.6 mg, 75%): 1H NMR (400 MHz,

CDCl3) δ 5.93 (d, J= 10.1 Hz, 1H), 3.66- 3.52(m, 2H), 3.49- 3.46 (m,2H), 2.74- 2.61 (m,

1H), 2.39 (s, 3H), 1.75- 1.63 (m, 1H), 1.43- 1.30 (m, 1H), 0.88 (s, 18H), 0.03 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 143.0, 95.5, 66.1, 60.8, 40.6, 34.3, 28.5, 26.2, 26.1, 18.5,

-5.2; HRMS (ESI+) calculated for C19H42O2Si2I: 485.1763, found: 485.1752; [α]D =

+28.5 (c= 1.2, CHCl3).

(+)-(S,2E,4E)-8-(tert-Butyldimethylsilyloxy)-6-((tert-butyldimethylsilyloxy)methyl)-4

-methylocta-2,4-dienoic acid (9): To a solution of vinyl iodide 34 (188.8 mg, 0.39 mmol)

and carboxylic acid 35 (288 mg, 0.779 mmol) in

N-methylpyrrolidinone (7 mL) was added

diisopropylethylamine (339 μL, 1.95 mmol) and Pd2dba3

(38 mg, 0.039 mmol) at room temperature under nitrogen. The flask was covered with

aluminum foil, and the reaction mixture was stirred overnight. The reaction was

quenched with saturated aqueous NH4Cl (20 mL) and extracted with Et2O (3 x 20 mL).

The combined organic layers were dried over Na2SO4, filtered, concentrated and the

product was purified by flash chromatography (eluent pentane/ether) to give 9 as a

colorless oil (145 mg, 87%): 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 15.6 Hz, 1H),

5.80 (d, J = 15.8 Hz, 1H), 5.75 (d, J = 12.4 Hz, 1H), 3.62-3.47 (m, 4H), 2.89-2.88 (m,

1H), 1.82 (s, 3H), 1.54-1.37 (m, 2H), 0.87 (s, 18H), 0.01 (s, 12H); 13C NMR (75 MHz,

CDCl3) δ 173.3, 152.0, 145.2, 134.3, 115.3, 66.3, 61.0, 38.6, 34.8, 26.1, 26.0, 18.4, 13.8,

12.8, -5.1, -5.2; HRMS (ESI+) calculated for C22H44O4Si2Na: 451.7432, found: 451.2652;

[α]D = +39.4 (c= 0.6, CHCl3).

(-)-(S,2E,4E)-((2R,3R)-2-((2S,4R,E)-4,6-Dimethyloct-6-en-2-yl)-6-oxo-3,6-dihydro-2

H-pyran-3-yl)-8-(tert-butyldimethylsilyloxy)-6-((tert-butyldimethylsilyloxy)methyl)-4

-methylocta-2,4-dienoate (36): To a solution of acid 9 (12.76 mg, 0.030 mmol, 1.5 eq)

in dry toluene (0.47 mL) was added HPLC grade

triethylamine (8.3 μL, 0.059 mmol, 3.0 equiv) at

room temperature followed by dropwise addition of

2,4,6-trichlorobenzoyl chloride (6.4 μL, 0.040

mmol, 2.0 equiv). The resulting solution was stirred

for 1 h upon which TLC showed complete conversion. Alcohol 8 (5.0 mg, 0.02 mmol, 1.0

eq) in dry toluene (0.5 mL) was then added, followed by DMAP (8.5 mg, 0.069 mmol,

3.5 equiv). After 2 h, the mixture was transferred to a silica gel column and eluted with

HO

O

OTBS

OTBS

OO

O

OOTBS

OTBS

Chapter 3

62

pentane/ether to yield 36 as a colorless oil (10.5 mg, 80%): 1H NMR (400 MHz, CDCl3)

δ 7.34 (d, J = 15.7 Hz, 1H), 7.04 (dd, J = 6, 9.6 Hz, 1H), 6.20 (d, J = 9.6 Hz, 1H), 5.77 (d,

J= 15.8 Hz, 1H), 5.73 (d, J= 5.5 Hz, 1H), 5.34 (dd, J= 2.4, 6.0 Hz, 1H), 5.11 (q, J = 7 Hz,

1H), 4.12 (dd, J= 2.4, 8.8 Hz, 1H), 3.63-3.44 (m, 4H), 2.89-2.78 (m, 1H), 2.22-2.13 (m,

1H), 2.05 (br d, J = 10.9 Hz, 1H), 1.79 (s, 3H), 1.74-1.61 (m, 1H), 1.52 (s, 3H), 1.48-1.36

(m, 1H), 1.30-0.94 (m, 11H), 0.87 (s, 9H), 0.86 (s, 9H), 0.78 (d, J = 6.5 Hz, 3H),

0.01-0.00 (m, 12H); 13C NMR (75 MHz, CDCl3): δ 166.6, 163.6, 151.8, 145.6, 140.8,

134.4, 134.2, 125.0, 120.3, 114.3, 83.5, 66.2, 61.9, 60.9, 46.6, 40.2, 38.6, 34.8, 31.7, 28.2,

26.1, 20.8, 18.5, 16.1, 15.5, 13.6, 12.8, -5.1 ; HRMS (ESI+) calculated for

C37H66O6Si2Na: 685.4290, found: 685.4245; [α]D = –157.1 (c= 0.5, CHCl3).

(-)-(S,2E,4E)-((2R,3R)-2-((2S,4R,E)-4,6-Dimethyloct-6-en-2-yl)-6-oxo-3,6-dihydro-2

H-pyran-3-yl)-8-hydroxy-6-(hydroxymethyl)-4-methylocta-2,4-dienoate (1): To a

solution of 36 (3.9 mg, 0.0059 mmol) in MeCN (1

mL) was added one drop of HF (48 wt.% in H2O) at

room temperature. The resulting mixture was stirred

for 20 min, and then quenched with saturated

aqueous NH4Cl (5 mL) and extracted with Et2O (3 x

5 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and

the product was purified by flash chromatography (eluent EtOAc/Heptane) to give 1 as a

colorless oil (2.6 mg, 100%): 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 15.7 Hz, 1H),

7.04 (dd, J = 5.9, 9.5 Hz, 1H), 6.21 (d, J = 9.6 Hz, 1H), 5.81 (d, J = 15.8 Hz, 1H), 5.77 (d,

J = 11.3 Hz, 1H), 5.35 (dd, J= 2.4, 6.0 Hz, 1H), 5.12 (q, J = 7 Hz, 1H), 4.12 (dd, J= 2.9,

6.7 Hz, 1H), 3.77- 3.71 (m, 1H), 3.65-3.57 (m, 2H), 2.93-2.84 (m, 1H), 2.25-2.13 (m,

1H), 2.05 (br d, J = 10.9 Hz, 1H), 1.84 (s, 3H), 1.80-1.75 (m, 1H), 1.71-1.66 (m, 1H),

1.65- 1.59 (m, 1H), 1.55 (d, J = 6.7 Hz, 3H), 1.53 (s, 3H), 1.44- 1.41 (m, 2H), 1.34- 1.24

(m, 5H), 1.15 (d, J = 6.6 Hz, 3H), 1.01, 0.78 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz,

CDCl3): δ 163.5, 160.7, 148.3, 140.7, 138.0, 132.1, 131.6, 122.4, 117.5, 112.5, 80.7, 63.3,

59.1, 58.1, 43.7, 37.4, 36.6, 32.1, 28.8, 27.7, 27.1, 18.0, 13.3, 10.8, 10.0; HRMS (ESI+)

calculated for C25H38O6Na: 457.2561, found: 457.2531; [α]D = –164.8 (c= 0.1, CHCl3)

[Lit.6= –162.8 (c=0.43, DCM), Lit.5b= –170 (c= 0.09, MeOH)]. The optical and

spectroscopic data are in agreement with the reported values.5,6

OO

O

OOH

OH

Chapter 3

63

2.6 References

1. (a) D. S. Lewy, C.-M. Gauss, D. R. Soenen, D. L. Boger, Curr. Med. Chem., 2002, 9, 2005. (b)

R. C. Jackson, D. W. Fry, T. J. Boritzki, B. J. Roberts, K. E. Hook, W. R. Leopold, Adv.

Enzyme Regul., 1985, 23, 193. (c) W. Scheithauer, D. D. von Hoff, G. M. Clark, J. L. Shillis,

E. F. Elslager, Eur. J. Clin. Oncol., 1986, 22, 921.

2. P. W. Reddell, V. A. Gordon, WO 2007070984 A1 20070628 PCT Int. Appl. 2007.

3. (a) M. A. Blazquez, A. Bermejo, M. C. Zafra-Polo, D. Cortes, Phytochem. Anal., 1999, 10,

161–170. (b) H. B. Mereyala, M. Joe, Curr. Med. Chem. Anti-Cancer Agents, 2001, 1,

293–300. (c) P. Tuchinda, B. Munyoo, M. Pohmakotr, P. Thinapong, S. Sophasan, T. Santisuk,

V. Reutrakul, J. Nat. Prod., 2006, 69, 1728–1733. (d) Z. Tian, S. Chen, Y. Zhang, M. Huang,

L. Shi, F. Huang, C. Fong, M. Yang, P. Xiao, Phytomedecine, 2006, 13, 181–186.

4. T. Tomikawa, K. Shin-Ya, K. Furihato, T. Kinoshita, A. Miyajima, H. Seto, Y. Hayakawa, J.

Antibiot., 2000, 53, 848.

5. (a) K. Akiyama, S. Kawamoto, H. Fujimoto, M. Ishibashi, Tetrahedron Lett., 2003, 44, 8427.

(b) K. Akiyama, S. Yamamoto, H. Fujimoto, M. Ishibashi, Tetrahedron, 2005, 61, 1827.

6. R. K. Boeckman, Jr., J. E. Pero, D. J. Boehmler, J. Am. Chem. Soc., 2006, 128, 11032.

7. R. Bhuniya, S. Nanda, Tetrahedron, 2013, 69, 1153–1165.

8. (a) R. D. Mazery, M. Pullez, F. López, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa, J.

Am. Chem. Soc., 2005, 127 , 9966. (b) B. ter Horst, B. L. Feringa, A. J. Minnaard, Chem.

Commun., 2010, 46, 2535.

9. (a) B. L. Feringa, B. D. Lange, J. C. de Jong, J. Org. Chem., 1989, 54, 2471. (b) A. van

Oeveren, B. L. Feringa, J. Org. Chem., 1996, 61, 2920. (c) A. van Oeveren, J. F. G. A. Jansen,

B. L. Feringa, J. Org. Chem., 1994, 59, 5999.

10. B. ter Horst, B. L. Feringa, A. J. Minnaard, Org. Lett., 2007, 9, 3013.

11. B. M. Trost, J. Waser, A. Meyer, J. Am. Chem. Soc., 2007, 129, 14556.

12. G. Zhu, E. Negishi, Chem. Eur. J., 2008, 14, 311.

13. O. Robles, F. E. McDonald, Org. Lett., 2009, 11, 5498.

14. G. E. Keck, C. E. Knutson, S. A. Wiles, Org. Lett., 2001, 3, 707.

15. S. F. Sabes, R. A. Urbanek, C. J. Forsyth, J. Am. Chem. Soc., 1998, 120, 2534.

16. J. A. Henderson, K. L. Jackson, A. J. Phillips, Org. Lett., 2007, 9, 5299

17. A. Furstner, T. Nagano, J. Am. Chem. Soc., 2007, 129, 1906.

18. (a) A. Barbero, F. J. Pulido, Chem. Soc. Rev., 2005, 34, 913–920. (b) M. G. Organ, S.

Bratovanov, Tetrahedron Lett., 2000, 41, 6945–6949.

19. Manfred Schlosser, Organometallics in Synthesis Third Manual, Wiley, 2013.

20. E. J. Corey, P. L. Fuchs, Tetrahedron Lett., 1972, 13, 3769–3772.

21. S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett, 1996, 521–522.

Chapter 3

64

22. J. Schwartz, J. A. Labinger, Angew. Chem. Int. Ed., 2003, 15, 330–340.

23. F. -Y. Yang, M. Shanmugasundaram, S. -Y. Chuang, P. -J. Ku, M. -Y. Wu, C.-H. Cheng, J. Am.

Chem. Soc., 2003, 125, 12576-12583.

24. M. F. Semmelhack, R. J. Hooley, Tetrahedron Lett., 2003, 44, 5737.

25. J. Thibonnet, V. Launay, M. Abarbri, A. Duchene, J. Parrain, Tetrahedron Lett., 1998, 39,

4277.

26. K. Ghosh, Y. Wang, J. T. Kim, J. Org. Chem., 2001, 66, 8973.

27. R. F. Newton, D. P. Reynolds, Tetrahedron Lett., 1979, 20, 3981.

Chapter 4

65

Chapter 4

A Novel Catalytic Asymmetric Route towards

Skipped Dienes with a Methyl‐Substituted

Central Stereogenic Carbon

In this chapter a highly efficient method for the enantioselective synthesis of 1,4-dienes

(skipped dienes) with a methyl-substituted central stereogenic carbon using

copper-catalyzed asymmetric allylic alkylation of diene bromides is described. Excellent

regio- and enantioselectivity (up to 97: 3 SN2’/SN2 ratio and 99% ee) were achieved with

broad substrate scope.

Parts of this chapter have been published: Y. Huang, M. Fañanás‐Mastral, A. J. Minnaard, B. L. Feringa, Chem. Commun., 2013, 49, 3309—3311.

Chapter 4

66

4.1 Introduction

Natural products containing 1,4-dienes (skipped dienes) such as polyunsaturated fatty

acids have important biological functions.1 Particular interesting molecules with a

1,4-diene bearing a methyl-substituted central stereogenic carbon include Hennoxazole

A,2 Ansalactam A,3 Ambruticin S,4 Iejimalide5 and Phorbasin E,6 shown in Figure 1

which are potent antibiotic, antifungal and cytotoxic agents.

Figure 1. Skipped polyenes found in diverse natural products.

4.2 Previous methodologies

The efficient preparation of these structural motifs remains a major challenge in organic

chemistry, although multi-step syntheses7 were reported. An elegant synthesis of the

above motif was reported by the group of Micalizio8 using a titanium-promoted reductive

cross-coupling reaction (Figure 2) between vinylcyclopropanes and alkynes (or

vinylsilanes). To the best of our knowledge, the only catalytic asymmetric synthesis of

the 3-methyl substituted 1,4-diene unit with broad substrate scope was reported by the

group of RajanBabu (Figure 3) by hydrovinylation of 1,3-dienes with excellent regio-

Chapter 4

67

and enantioselectivity.9

Figure 2. Reductive cross‐coupling of vinylcyclopropanes with alkynes or vinylsilanes.

Figure 3. Hydrovinylation of 1,3‐dienes.

Some examples have been reported in the literature for the synthesis of related structures

using copper-catalysed asymmetric allylic alkylation (AAA)10 mainly with longer alkyl

chains at the central position. The group of Hoveyda (Figure 4) described a

copper-catalysed AAA of allylic phosphates with diethylzinc reagent using peptide-based

ligand L7 including one example of a skipped diene.11 Li and Alexakis (Figure 5)

reported an copper-catalyzed asymmetric allylic substitution of enyne chlorides with

Grignard reagents which was also extended to two diene chlorides for the synthesis of

3-ethyl and 3-phenethyl substituted skipped dienes.12 Recently Mauduit et.al. reported a

single example of a 3-methyl substituted skipped diene using copper-catalyzed AAA of

diene allylic phosphates with dimethylzinc (Figure 6).13 Since the introduction of a

methyl branch remains a highly wanted goal in view of its importance in natural product

synthesis, we report here a highly efficient catalytic methodology to prepare this

structural motif with broad substrate scope and excellent enantioselectivity using

copper-catalysed AAA of diene bromides with the readily available methylmagnesium

bromide (Figure 7).

Chapter 4

68

Figure 4. Hoveyda’s approach.

Figure 5. Alexakis’s approach.

Figure 6. Mauduit’s approach.

Figure 7. Goal of my research.

4.3 Synthesis of Starting materials

To explore the substrate scope of the reaction, a series of linear non-branched E,E-diene

allylic bromides were synthesized followed by some methyl-branched ones. Finally two

substrates with different double bond geometry were prepared.

Synthesis of linear non-branched substrate 1a

The first substrate 1a (Figure 8) was prepared from commercial available E,E-diene acid

4. Initial reduction of the acid 4 using LiAlH4 and borane resulted in complicated

products or reduction of the double bond. Switching to a two step sequence via the

preparation of the methyl ester 5 followed by reduction using DIBAL gave the allyl

alcohol 6 in good yield. Bromination of 6 with NBS and dimethyl sulfide gave the

desired product 1a in high yield.

Chapter 4

69

Figure 8. Synthesis of phenyl substituted E,E‐diene bromide 1a.

Synthesis of linear non-branched substrate 1b

The synthesis of substrate 1b (Figure 9) started with Horner–Wadsworth–Emmons

reaction of aldehyde 7 and a E/Z-mixture of phosphonate 8 to give E,E-diene ester 9 in

62% yield. Reduction of ester 9 using DIBAL afforded allyl alcohol 10 in high yield.

Initial bromination using PBr3 gave an E/Z mixture of 1b (E/Z=90/10), fortunately,

employing NBS and dimethyl sulfide improved the result and no isomerization of the

double bond occurred.

Figure 9. Synthesis of E,E‐diene bromide 1b.

Synthesis of linear non-branched substrate 1c

The first attempt to prepare 1c (Figure 10) started from esterification of 11 to form

methyl ester 12 followed by the radical reaction using NBS and AIBN, however,

complicated products were obtained. Fortunately alkene metathesis using allyl bromide

13 gave the desired product 1c.

Chapter 4

70

Figure 10. Synthesis of E,E‐diene bromide 1c.

Synthesis of linear non-branched substrate 1d

Synthesis of substrate 1d (Figure 11) started from acid 14. Esterification of acid 14 using

HCl and methanol gave di-ester 15 in high yield followed by reduction using DIBAL to

form diol 16. Mono-protection of diol 16 using TBSCl afforded alcohol 17 in moderate

yield. First attempt to prepare 1d using PBr3 failed probably due to the acidity of the

reaction media. Employing NBS and dimethyl sulfide, the desired product 1d was

obtained in high yield.

HCl, MeOH

r.t., o.n.86%

OH

O

O

HOO

O

O

O

DIBAL

DCM, -78oC83%

OTBSHO

TBSCl,imidazole

DMF, rt, 16h53% after 2 columns

NBS, Me2S

DCM, -20oC85%

OTBSBr

OHHO

PBr31d

14 15 16

17

Figure 11. Synthesis of E,E‐diene bromide 1d.

Synthesis of linear methyl-branched substrate 1e

The synthesis of substrate 1e (Figure 12) started from the preparation of diol 19. Initial

reduction of di-ester 18 using DIBAL resulted in low yield with large amounts of an

unknown product. While LiAlH4 gave fully reduced product 20. It’s interesting to see that

reduction of internal alkyne 21 using LiAlH4 stereoselectively gave E-diol 19 in high

yield. Mono-esterification of diol 19 gave alcohol 22 followed by PCC oxidation to form

the aldehyde 23. Wittig reaction of aldehyde 23 and ylide 24 gave diene ester 25 in

overall 64% yield for above 2 steps. Mild hydrolysis of the acetate group using K2CO3 in

ethanol afforded the desired alcohol 26 in 93% yield. Final bromination using NBS and

dimethyl sulfide gave the desired product 1e.

Chapter 4

71

Figure 12. Synthesis of E,E‐diene bromide 1e.

Synthesis of linear methyl-branched substrate 1f

Substrate 1f (Figure 13) was synthesized from Horner–Wadsworth –Emmons reaction of

methyl ketone 27 and phosphonate 28 in water to form ester 29 as a mixture of isomers

(E/Z=2/1). HCl promoted hydrolysis of the acetal group and isomerization of the internal

double bond formed the aldehyde 30 which was followed by Wittig reaction with ylide

31 gave aldehyde 32. Aldehyde 32 was used immediately for reduction using NaBH4 to

alcohol 33. Bromination of 33 gave the desired product 1f in high yield.

Chapter 4

72

Figure 13. Synthesis of E,E‐diene bromide 1f.

Synthesis of linear methyl-branched substrate 1g by Stille cross coupling

The initial synthesis of vinyltin alcohol 36 started from radical reaction of alcohol 38

using AIBN and tributyltin hydride without any solvent.14 However, the reaction gave

complicated products. Similar results were obtained using hexane and benzene as the

solvent. Stannyl cupration15 using CuCN, tributyltin hydride and butyllithium and

palladium catalyzed hydrostannation16 gave no conversion at all. Surprising to see that

changing from tributyltin hydride to bis-tributyltin (Figure 14),17 the stannyl cupration

gave full conversion in 4 h although providing a mixture of regioisomers (36/39=1/1).

Figure 14. Synthesis of vinyltin alcohol 36.

Due to a separation problem of above regioisomers, a Piers’ modification18 was

performed (Figure 15). Stannyl cupration using CuBr•SMe2 instead of CuCN on alkyne

40 selectively gave the E-vinyltin 41 in quant. yield. Reduction of the vinyltin ester 41

using DIBAL afforded the desired vinyltin alcohol 36 in high yield.

Figure 15. Piers’ modification of stannyl cupration.

The substrate 1g (Figure 16) was prepared from the synthesis of Z-vinyliodide 35 from

ester 34 using LiI in acetic acid in high yield. Initial Stille cross coupling of iodide 35 and

Chapter 4

73

vinyltin 36 using Pd2dba3 in NMP gave a mixture of stereoisomers of 37 due to the

double bond isomerization catalyzed by palladium. However, a catalytic amount of

triphenyl arsine18 improved the result considerably as no isomerization occurred. And the

product 37 could be obtained in 76% yield. Final bromination of 37 using NBS and

dimethyl sulfide gave the substrate 1g in good yield.

Figure 16. Synthesis of diene bromide 1g.

Attempted synthesis of linear methyl-branched substrate 1h

The synthesis of substrate 1h (Figure 17) started from alkyne 38. Zr-catalyzed

methylalumination of 38 gave vinyl iodide 42 followed by protection to form compound

43. Stille cross coupling of vinyl tin 41 and vinyl iodide 43 gave diene ester 44 in good

yield. Reduction of the ester group by DIBAL afforded the allyl alcohol 45 in 80% yield.

However, all attempts to synthesize 1h failed probably due to its instability.

Figure 17. Attempted synthesis of substrate 1h.

Attempted synthesis of linear methyl-branched substrate 1i

The synthesis of substrate 1i (Figure 18) started with the preparation of vinyl iodide 48

from alkyne 46. The first attempt using palladium catalyzed hydrostannation gave no

Chapter 4

74

conversion at all. The classic Schwartz’s hydrozirconation19 (the Schwartz’s reagent was

prepared from Cp2ZrCl2 and LiAlH4) gave a mixture of regioisomers (48/49=1/1).

Fortunately, the Negishi’s modification20 (the Schwartz’s reagent was prepared from

Cp2ZrCl2 and DIBAL) improved the result a lot, only the desired regioisomer 48 was

obtained. Stille cross coupling of vinyl iodide 48 and vinyl tin 41 gave the desired diene

ester 50 in 89% yield. Reduction of the ester 50 using DIBAL formed the allyl alcohol 51.

However, all attempts towards the synthesis of the substrate 1i failed probably due to the

instability of the substrate. Although the synthesis of substrates 1h and 1i failed, the

corresponding products after AAA (skipped dienes) could be easily made by the AAA of

esters 1e and 1f followed by reduction and protection.

Figure 18. Attempted synthesis of substrate 1i.

4.4 Results of the Cu-catalyzed AAA and discussion

Our investigation started with the asymmetric allylic alkylation of 1a with MeMgBr in

dichloromethane at –80 oC employing copper bromide dimethylsulfide complex

(CuBr•SMe2) and L1 as ligand (Table 1, entry 1). Product 2a was isolated in 65% yield

with 85% ee and the ratio of 2a:3a (SN2’/SN2) was 79:21. To increase both the regio- and

enantioselectivity of the reaction, a series of catalysts based on the chiral ligands depicted

in Table 1 was tested. Both Tol-BINAP (L2) and JosiPhos type ligands (L4 and L5)

afforded lower ee than L1. We then used the combination of CuBr•SMe2 with TaniaPhos

(L3), which has emerged as an excellent catalyst for the introduction of the methyl unit

via copper-catalysed AAA.21 We were pleased to see that the use of this catalytic system

led to product 2a in 66% yield with >99% ee and with excellent regioselectivity (2a:3a =

Chapter 4

75

95:5). It is important to note that only 1,3-substitution happened and no 1,5-substitution

adduct was detected.

Table 1. Optimization of the copper‐catalysed AAA of 1a.

CuBr•SMe2 5 mol%Ligand 6 mol%

MeMgBr 1.2 equiv

DCM, -80 oC, o.n.

Br

1a 2a 3a

+

Fe

O

OP N

Ph

Ph

(S,R,R)-L1

(S,S)-TaniaPhos L3

(R)-Tol-BINAP L2

Fe

P(Tol)2P(Tol)2

(R,S) -Josiphos L4

PPh2NPh2P

PPh2

PCy2

FeCy2P

Ph2P

(S,R)-rev. Josiphos L5 Entrya Ligand Solvent Yield [%]b SN2’/SN2

c ee [%]d

1 L1 DCM 65 79:21 85

2 L2 DCM 68 36:64 ‐50f

3 L3 DCM 66 95:5 >99

4 L4 DCM 75 50:50 ‐62f

5 L5 DCM 51 23:77 32

6 L3 Toluene 25e 80:20 95

7 L3 THF 34e 91:9 87

8 L3 Et2O 46e 8:92 71

aReaction conditions: MeMgBr (0.3 mmol) was added to a stirred solution of CuBr•SMe2 and ligand in dry

solvent at –80 oC; 1a (0.25 mmol) in 1 mL of dry solvent was added dropwise over 1 h.

bisolated combined yield.

cdetermined by

1H NMR or GC.

ddetermined by chiral GC.

emixture of products.

fThe negative ee value indicates

that the opposite enantiomer was formed.

With this highly selective catalyst in hand, we studied the solvent effects on the reaction.

We found that dichloromethane was still the most effective solvent. When we used

toluene, product 2a was obtained with 95% ee but with lower regioselectivity (Table 1,

entry 6). The use of THF gave comparable regioselectivity as DCM but the ee decreased

to 87% (entry 7). The situation in diethyl ether was even worse; the enantioselectivity

decreased and the regioselectivity was totally switched, with linear product 3a being the

main product of the reaction (entry 8). To study the scope of this new enantioselective

Chapter 4

76

transformation, previous synthesized substrates were tested under the optimized

conditions (Table 1, entry 3). Excellent regio- and enantioselectivity were obtained in all

cases (Figure 19).

Figure 19. Copper‐catalysed AAA of diene bromides 1. Reaction conditions: MeMgBr (0.3

mmol) was added to a stirred solution of CuBr•SMe2 and TaniaPhos (L3) in dry DCM at –80 oC;

substrate 1 (0.25 mmol) in 1 mL of dry DCM was added dropwise over 1 h. Yield represents

combined isolated yield. Regioselectivity was determined by 1H NMR or GC analysis. Ee was

determined by chiral GC or HPLC. a1 g scale, 1 mol% of catalyst; 58% yield, SN2’/SN2 95:5, 99% ee. bVolatile products

This new methodology proved to be also very efficient for an alkyl substituted substrate

such as 1b (R1 = iso-Bu) which afforded 1,4-diene 2b with excellent selectivity. It should

be noted that product 2b represents the side chain of Phorbasins (Figure 1). Notably, both

the regio- and enantioselectivity of the reaction dropped considerably when we used a

(2E,4E)/(2Z,4E) isomeric mixture of substrate 1b. The E-geometry of the double bond

next to the bromide seems crucial for achieving high ee and regioselectivity (Figure 20).

A remarkable result was obtained with ester-substituted diene bromide 1c which led

exclusively to product 2c, without any traces of the 1,2-, 1,4- or 1,6-addition to the

carbonyl moiety nor of the 1,5-substitution product. Moreover, product 2c is a core unit

of Iejimalides (Figure 1). The versatile substituent TBSOCH2, as present in diene 1d, had

no influence on the enantioselectivity and diene 2d could be obtained with 99% ee

although a slightly lower regioselectivity was observed. The more substituted substrates

Chapter 4

77

1e and 1f, with methyl groups at R2 or R3, could also be used in this transformation.

Again, 2e and 2f were obtained exclusively with excellent selectivity. We also tested the

effect of the remote double bond geometry as the presence of a Z-double bond is common

in some natural products like Hennoxazole A. We were pleased to find that the reaction

also proceeded succesfully with (Z,E)-1g affording similar regio- and enantioselectivity

as with (E,E)-1f, while no double bond isomerization was detected in 2g. These

remarkable results show that the geometry of the double bond remote from the bromide

seems to have no effect on both the regio- and enantioselectivity (Figure 20). An

important feature is the scalability of this reaction. Synthesis of 2a was executed on a

larger scale (1 gram) using only 1 mol% of catalyst and still excellent ee and

regioselectivity were obtained, with similar yield.

Figure 20. Effect of double bond geometry on ee and regioselectivity.

Finally we tried further functionalization of the 1,4-diene 2d via cross metathesis22

(Figure 21) for future synthetic applications. The initially attempted cross metathesis with

ethyl acrylate 52 using Grubbs’ first and second-generation catalysts and

Hoveyda–Grubbs first-generation catalyst under different conditions led to complicated

products. However, Hoveyda–Grubbs second-generation catalyst significantly improved

the outcome and afforded the product 53 as single E,E-isomer. The presence of a

protected alcohol and ester group facilitates the use of optically active 53 as a versatile

multifunctional building block in natural product synthesis allowing for chain elongation

on each end of the molecule.

Figure 21. Cross metathesis between 1,4‐diene 2d and ethyl acrylate 52.

Chapter 4

78

4.5 Conclusion

In summary, a copper-catalysed asymmetric allylic alkylation with methylmagnesium

bromide as nucleophile employing prochiral diene allylic bromides as substrates was

developed. The reaction leads to important chiral 3-methyl substituted 1,4-diene building

blocks with excellent regio- and enantioselectivity (ee values up to 99%; SN2’/SN2 ratio

up to 97:3) in nearly all cases. Application of this methodology to the total synthesis of

Phorbasins B is ongoing (Chapter 5).




and distilled prior to use. All reactions were carried out under a nitrogen atmosphere

using oven dried glassware and using standard Schlenk techniques. Column

chromatography was performed on silica gel (Aldrich 60, 230-400 mesh). TLC was

performed on silica gel 60/Kieselguhr F254. 1H and 13C NMR spectra were recorded on a Varian VXR300 (299.97 MHz for 1H, 75.48



(ppm) relative to the residual solvent peak (CDCl3, 1H = 7.24, 13C = 77.0). Carbon






g/100 mL). Enantiomeric excesses were determined by HPLC analysis using a Shimadzu

LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector

(Chiralcel OD-H, 250*4.6, 10 μm) or by capillary GC analysis (HP 6890,

CP-Chiralsil-Dex-CB column (25 m * 0.25 mm)) using a flame ionization detector.

Racemic products were synthesized by reaction of the allyl bromide and the

corresponding organomagnesium reagent at –80 °C in dry dichloromethane in the

presence of CuBr•SMe2 (10 mol%) and PPh3 (20 mol%).

Chapter 4

79

(2E,4E)-Methyl-5-phenylpenta-2,4-dienoate (5).23 To a stirred solution of

5-phenylpenta-2,4-dienoic acid 4 (3.91 g, 22.4 mmol) in 50 mL

of methanol was added HCl (20 ml, 60 mmol, 3M in methanol)

at room temperature. The solution was stirred for 16 h,

concentrated and purified by flash chromatography (eluent pentane/ether = 10/1) to give

5 as a white solid (4.07 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.21 (m, 6H),

6.87 – 6.73 (m, 2H), 5.93 (d, J = 15.3 Hz, 1H), 3.70 (s, 3H); 13C NMR (101 MHz, CDCl3)

δ 167.5, 144.8, 140.5, 136.0, 129.0, 128.8, 127.2, 126.2, 120.8, 51.6.

(2E,4E)-5-Phenylpenta-2,4-dien-1-ol (6).23 To a stirred solution of the methyl ester 5

(4.00 g, 21.2 mmol) in 50 mL of dry DCM was added

DIBAL-H (63.8 ml, 1 M in DCM, 63.8 mmol, 3 eq) over 0.5 h

at –78 oC. The reaction mixture was stirred for 4 h when TLC

showed full conversion. The mixture was quenched with 60 mL of saturated aqueous

Rochelle salt (potassium sodium tartrate) and stirred for 30 min. The phases were

separated and the aqueous layer was extracted with DCM (3 x 50 mL). The combined

organic phases were dried over Na2SO4, filtered, concentrated and purified by flash

chromatography (eluent pentane/ether = 4/1) to give 6 as a white solid (3.0 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.05 (m, 5H), 6.72 (dd, J = 15.6, 10.5 Hz, 1H), 6.49

(d, J = 15.6 Hz, 1H), 6.36 (dd, J = 15.1, 10.5 Hz, 1H), 5.90 (dt, J = 15.1, 5.9 Hz, 1H),

4.19 (d, J = 5.9 Hz, 2H), 1.31 (br, 1H); 13C NMR (101 MHz, CDCl3) δ 137.1, 132.8,

132.4, 131.6, 128.6, 128.1, 127.6, 126.4, 63.5.

((1E,3E)-5-Bromopenta-1,3-dienyl)benzene (1a). To a stirred solution of NBS (4.17 g,

23.4 mmol, 1.3 eq) in DCM (40 mL) at –20 oC was added Me2S

(0.980 g, 1.2 mL, 28.9 mmol, 1.83 eq) slowly over 5 min. The

reaction mixture was stirred for 15 min before a solution of

allylic alcohol 9 (2.50 g, 15.6 mmol) in 10 mL of DCM was added dropwise over 10 min.

The mixture was quenched with a saturated aqueous NH4Cl solution (50 mL) when TLC

showed full conversion and after the mixture was warmed up to room temperature, the

layers were separated. The organic layer was washed with water (3 x 20 mL), dried over

Na2SO4, filtered and concentrated to give crude 1a as a white solid (2.83 g, 81%) which

was used in the next step (asymmetric allylic alkylation) immediately due to instability. 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.15 (m, 5H), 6.77 (dd, J = 15.6, 10.4 Hz, 1H), 6.60

(d, J = 15.6 Hz, 1H), 6.46 (dd, J = 14.8, 10.4 Hz, 1H), 6.08 – 5.90 (m, 1H), 4.11 (d, J =

8.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 136.7, 135.2, 134.5, 128.9, 128.7, 128.0,

127.3, 126.6, 33.4.

O

O

OH

Br

Chapter 4

80

(2E,4E)-Ethyl‐7-methylocta-2,4-dienoate (9).24 To a stirred solution of compound 8

(mixture of E/Z isomers, 5.0 g, 20 mmol) in 30 mL of dry

THF was added LiHDMS (20 mL, 20 mmol, 1M in THF) at

–78 oC under nitrogen. The mixture was stirred for about 30

min when a THF solution (5 mL) of aldehyde 7 (1.72 g, 20 mmol, 1 eq) was added

dropwise over 10 min. The resulting solution was stirred overnight and quenched with a

saturated aqueous NH4Cl solution (50 mL) at –78 oC. The mixture was warmed up to

room temperature and the layers were separated. The aqueous layer was washed with

ether (3 x 30 mL) and the organic layers were dried over Na2SO4, filtered and

concentrated and purified by flash chromatography (eluent pentane/ether = 10/1) to give

9 as a colorless oil (2.3 g, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.12 (m, 1H),

6.17 – 5.94 (m, 2H), 5.72 (d, J = 15.5 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.01 – 1.97 (m,

2H), 1.66 – 1.63 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 0.84 (d, J = 6.7 Hz, 6H); 13C NMR

(101 MHz, CDCl3) δ 167.3, 145.0, 143.5, 129.4, 119.2, 60.2, 42.3, 28.3, 22.3, 14.3.

(2E,4E)-7-Methylocta-2,4-dien-1-ol (10). To a stirred solution of the ethyl ester 9 (2.0 g,

11 mmol) in 30 mL of dry DCM was added DIBAL-H (33 ml, 1

M in DCM, 33 mmol, 3 eq) over 0.5 h at –78 oC. The reaction

mixture was stirred for 4 h when TLC showed full conversion.

The reaction mixture was quenched with 30 mL saturated aqueous Rochelle salt

(potassium sodium tartrate) and stirred for 30 min. The phases were separated and the

aqueous layer was extracted with DCM (3 x 30 mL). The combined organic phases were

dried over Na2SO4, filtered, concentrated and purified by flash chromatography (eluent

pentane/ether = 4/1) to give 10 as a colorless oil (1.5 g, 95% yield). 1H NMR (400 MHz,

CDCl3) δ 6.23 (dd, J = 15.1, 10.4 Hz, 1H), 6.03 (dd, J = 15.1, 10.4 Hz, 1H), 5.81 – 5.63

(m, 2H), 4.16 (dd, J = 6.1, 0.9 Hz, 2H), 2.02 – 1.92 (m, 2H), 1.65 – 1.62 (m, 1H), 1.38 (br,

1H), 0.89 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 134.5, 132.1, 130.4, 129.3,

63.5, 42.0, 28.5, 22.3. HRMS (APCI+) calculated for C9H15[M–OH]+: 123.1174, found:

123.1116.

(2E,4E)-1-Bromo-7-methylocta-2,4-diene (1b). To a stirred solution of NBS (1.07 g, 6

mmol, 1.3 eq) in DCM (20 mL) at –20 oC was slowly added

Me2S (460 mg, 0.54 mL, 7.4 mmol, 1.83 eq) over a 5 min period.

The reaction mixture was stirred for 15 min before a solution of

allylic alcohol 10 (560 mg, 4 mmol) in 10 mL of DCM was added dropwise over 10 min.

The mixture was quenched with a saturated aqueous NH4Cl solution (50 mL) when TLC

OH

Br

Chapter 4

81

showed full conversion and after the mixture was warmed up to room temperature, the

layers were separated. The organic layer was washed with water (3 x 20 mL), dried over

Na2SO4, filtered and the solvent was concentrated to give crude 1b as colorless oil (0.69

g, 85%) used in the next step immediately due to instability. 1H NMR (400 MHz, CDCl3)

δ 6.32 – 6.07 (m, 1H), 5.99 – 5.88 (m, 1H), 5.78 – 5.63 (m, 2H), 4.02 – 3.85 (m, 2H),

1.96 – 1.87 (m, 2H), 1.60 – 1.57 (m, 1H), 0.82 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz,

CDCl3) δ 136.5, 135.4, 129.8, 126.1, 42.0, 33.9, 28.4, 22.3.

(2E,4E)-Methyl-hexa-2,4-dienoate (12).25 To a stirred solution of acid 11 (4.0 g, 36

mmol, 1 eq) in 50 mL of methanol was added HCl (24 mL, 72 mmol,

3M in methanol, 2 eq) at room temperature. The resulting solution

was stirred for 16 h, concentrated and purified by flash

chromatography (eluent pentane/ether = 10/1) to give 12 as colorless oil (4.22 g, 93%

yield). 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.10 (m, 1H), 6.19 – 5.98 (m, 2H), 5.71 (d, J

= 15.4 Hz, 1H), 3.67 (s, 3H), 1.78 (d, J = 5.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ

167.8, 145.2, 139.4, 129.7, 118.5, 51.4, 18.6.

(2E,4E)-Methyl‐6-bromohexa-2,4-dienoate (1c).26 To a solution of methyl sorbate 12

(1.0 g, 8 mmol) and allyl bromide 13 (4.84 g, 40 mmol, 5 eq) in

80 mL of CH2Cl2 (c = 0.1 M) was added the Hoveyda-Grubbs-II

catalyst (C11H38Cl2N2ORu, 50 mg, 0.08 mmol, 0.01 equiv) at

room temperature. After stirring for 24 h, silica was added to the reaction mixture and

after evaporation of the solvent, the pad of silica was loaded on top of a silica gel column

and the product was quickly purified by a flash chromatography (eluent pentane/ether =

4/1) to give 1c as a colorless oil (483 mg, 30% yield). 1H NMR (400 MHz, CDCl3) δ 7.32

– 7.21 (m, 1H), 6.39 (dd, J = 15.0, 10.9 Hz, 1H), 6.24 (dd, J = 15.4, 10.9 Hz, 1H), 5.94 (d,

J = 15.4 Hz, 1H), 4.06 – 3.99 (m, 2H), 3.75 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.9,

142.8, 136.7, 131.8, 122.7, 51.7, 31.2.

(2E,4E)-Dimethyl‐hexa-2,4-dienedioate (15).27 To a stirred solution of acid 14 (4.0 g,

28 mmol) in 50 mL of methanol was added HCl (19 mL, 57

mmol, 3M in methanol, 2 eq) at room temperature. The

resulting solution was stirred for 16 h, concentrated and purified

by crystallization from ether to give 15 as a white solid (4.13 g, 86% yield). 1H NMR

(400 MHz, CDCl3) δ 7.33 – 7.21 (m, 2H), 6.21 – 6.07 (m, 2H), 3.72 (s, 6H); 13C NMR

(101 MHz, CDCl3) δ 166.3, 140.9, 128.0, 51.9.

O

O

O

OBr

O

O

O

O

Chapter 4

82

(2E,4E)-Hexa-2,4-diene-1,6-diol (16).28 To a stirred solution of the methyl ester 15 (1.0

g, 5.9 mmol) in 30 mL of dry DCM was added DIBAL-H (36 ml,

1 M in DCM, 36 mmol, 6 eq) over 0.5 h at –78 oC. The reaction

mixture was stirred for 8 h when TLC showed full conversion. The reaction mixture was

quenched with 30 mL saturated aqueous Rochelle salt (potassium sodium tartrate)

followed by stirring for 30 min. The phases were separated and the aqueous layer was

extracted with DCM (3 x 30 mL). The combined organic phases were dried over Na2SO4,

filtered, concentrated and purified by flash chromatography (eluent pentane/EtOAc = 2/1)

to give 16 as a white solid (560 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 6.30 –

6.08 (m, 2H), 5.91 – 5.66 (m, 2H), 4.14 (t, J = 5.4 Hz, 4H), 1.29 (t, J = 5.4 Hz, 2H); 13C

NMR (101 MHz, CDCl3) δ 132.4, 130.4, 63.2.

(2E,4E)-6-((tert-Butyldimethylsilyl)oxy)hexa-2,4-dien-1-ol (17).29 To a solution of 16

(300 mg, 2.63 mmol) in dry dichloromethane (20 mL) was

added imidazole (269 mg, 3.95 mmol, 1.5 eq) followed by

tert-butyl-dimethylsilyl chloride (436 mg, 2.89 mmol, 1.1 eq), and the resulting white

suspension was stirred at room temperature for 12 h. The reaction mixture was quenched

with 20 mL of water and extracted with ether (3 x 20 mL). The combined organic layers

were dried over Na2SO4, filtered, concentrated and purified by flash chromatography

(eluent pentane/EtOAc = 4/1) to give 17 as a colorless oil (319 mg, 53%). 1H NMR (400

MHz, CDCl3) δ 6.24 – 6.11 (m, 2H), 5.81 – 5.65 (m, 2H), 4.15 (d, J = 4.5 Hz, 2H), 4.11 (t,

J = 5.6 Hz, 2H), 1.50 (br, 1H), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (101 MHz, CDCl3) δ

133.3, 131.4, 131.0, 128.8, 63.4, 63.3, 25.9, 18.4, –5.2.

((2E,4E)-6-Bromohexa-2,4-dienyloxy)(tert-butyl)-dimethyl silane (1d). To a stirred

solution of NBS (267 mg, 1.5 mmol, 1.5 eq) in DCM (20 mL)

at –20 oC was slowly added Me2S (115 mg, 0.14 mL, 1.85

mmol, 1.85 eq) over a 5 min period. The reaction mixture was stirred for 15 min before a

solution of allylic alcohol 17 (228 mg, 1 mmol) in 5 mL of DCM was added dropwise

over 10 min. The mixture was quenched with a saturated aqueous NH4Cl solution (20 mL)

when TLC showed full conversion and subsequently the mixture was warmed up to room

temperature and the layers separated. The organic layer was washed with water (3 x 10

mL), dried over Na2SO4, filtered and concentrated to give the crude 1d as colorless oil

(248 mg, 85%) immediately used in the next step due to instability. 1H NMR (400 MHz,

CDCl3) δ 6.29 – 6.10 (m, 2H), 5.77 (m, 2H), 4.16 (dd, J = 5.0, 1.1 Hz, 2H), 3.96 (d, J =

7.9 Hz, 2H), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 135.2, 134.4,

127.9, 127.9, 63.1, 33.3, 25.9, 18.1, –5.3.

OHHO

OTBSHO

OTBSBr

Chapter 4

83

(E)-But-2-ene-1,4-diol (21).30 To a stirred solution of diol 19 (2.6 g, 30 mmol) in dry

THF (40 mL) was added solid LiAlH4 (1.44 g, 36 mmol, 1.2 eq) at 0 oC under nitrogen. The mixture was heated to reflux for 4 h, followed

by quenching with a saturated aqueous NH4Cl solution (20 mL) at 0 oC. The mixture was

allowed to warm to room temperature and the phases were separated. The aqueous layer

was extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over


pentane/EtOAc = 1/1) to give 21 as colorless oil (660 mg, 20% yield, soluble in water). 1H NMR (400 MHz, CDCl3) δ 5.89 – 5.79 (m, 2H), 4.17 – 4.05 (m, 4H), 1.38 (br, 2H); 13C NMR (101 MHz, CDCl3) δ 130.5, 62.9.

(E)-4-Hydroxybut-2-en-1-yl acetate (22).31 To a stirred solution of but-2-ene-1,4-diol

21 (1.0 g, 11 mmol) in dry THF (20 mL) was added solid NaH (440

mg, 60% in mineral oil, 11 mmol, 1 eq) at 0 oC. The mixture was

stirred at room temperature for 1 h followed by the addition of a THF solution (5 mL) of

acetyl chloride (863 mg, 0.81 mL, 1 eq). The reaction mixture was stirred for 3 h after

which time TLC (diethyl ether) showed a mixture of starting compound, monoacetate

and diacetate. H2O (10 mL) was added, and the mixture was extracted with diethyl ether

(3 x 30 mL). The combined organic phases were dried over Na2SO4, filtered,

concentrated and purified by flash chromatography (eluent pentane/EtOAc = 4/1) to give

22 as colourless oil (930 mg, 65% yield). 1H NMR (400 MHz, CDCl3) δ 5.93 – 5.81 (m,

1H), 5.80 – 5.73 (m, 1H), 4.52 (dd, J = 5.8, 1.2 Hz, 2H), 4.12 (dd, J = 5.0, 1.2 Hz, 2H),

2.01 (s, 3H), 1.63 (br, 1H); 13C NMR (101 MHz, CDCl3) δ 171.6, 133.5, 125.1, 64.2,

62.7, 20.9.

(2E,4E)-Ethyl-6-acetoxy-2-methylhexa-2,4-dienoate (25).31 4-Acetoxy- 2-buten-1-ol

22 (0.91 g, 7 mmol) was added to a suspension of pyridinium

chlorochromate (1.81 g, 8.4 mmol) in 20 mL of DCM at 0 °C.

The mixture was stirred at room temperature until TLC showed

full conversion. The solids were removed by flash chromatography, washed with diethyl

ether and the organic solvents were removed in vacuo to give 4-acetoxy-crotonaldehyde

23 used immediately in the next step.

The aldehyde 23 was dissolved in 10 mL of DCM followed by the addition of

phosphorane 24 (2.54 g, 7.0 mmol) at room temperature. The solution was stirred for 30

min until TLC showed full conversion. The solvent was removed in vacuo. The product

was purified by flash chromatography (eluent pentane/ether = 4/1) to give 25 as colorless

OHHO

OAcHO

OAcEtO

O

Chapter 4

84

oil (945 mg, 64% yield over 2 steps). 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 11.4 Hz,

1H), 6.58 – 6.45 (m, 1H), 6.02 (dt, J = 15.2, 6.1 Hz, 1H), 4.62 (d, J = 6.1 Hz, 2H), 4.15

(q, J = 7.1 Hz, 2H), 2.03 (s, 3H), 1.88 (d, J = 0.7 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

(2E,4E)-Ethyl-6-hydroxy-2-methylhexa-2,4-dienoate (26).31 K2CO3 (1.23 g, 8.9 mmol)

was added to a solution of 25 (945 mg, 4.45 mmol) in 15 mL of

ethanol at room temperature. The resulting mixture was stirred

about 2 h when TLC showed full conversion. The reaction was

quenched with an aqueous saturated NaCl solution (20 mL). The phases were separated

and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic

phases were dried over Na2SO4, filtered, concentrated and purified by flash

chromatography (eluent pentane/EtOAc = 4/1) to give 26 as colourless oil (707 mg, 93%

yield). 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 11.4 Hz, 1H), 6.53 (dd, J = 15.2, 11.4

Hz, 1H), 6.11 (dt, J = 15.2, 5.2 Hz, 1H), 4.28 – 4.20 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H),

1.89 (d, J = 0.7 Hz, 3H), 1.45 (br, 1H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,

CDCl3) δ 168.4, 139.2, 137.1, 127.8, 125.7, 63.1, 60.6, 14.3, 12.7.

(2E,4E) -Ethyl- 6- bromo -2- methylhexa-2,4-dienoate (1e). To a stirred solution of

NBS (470 mg, 2.64 mmol, 1.3 eq) in DCM (20 mL) at –20 oC

was slowly added Me2S (197 mg, 0.23 mL, 3.17 mmol, 1.83 eq)

over a 5 min period. The reaction mixture was stirred for 15 min

before a solution of allylic alcohol 26 (300 mg, 1.76 mmol) in 5 mL of DCM was added

dropwise over 10 min. The mixture was quenched with a saturated aqueous NH4Cl

solution (50 mL) when TLC showed full conversion and after the mixture was warmed to

room temperature, the layers were separated. The organic layer was washed with water (3

x 10 mL), dried over Na2SO4, filtered and concentrated to give the crude 1e as colorless

oil (323 mg, 79%) used in the next step immediately due to instability. 1H NMR (400

MHz, CDCl3) δ 7.09 (dd, J = 11.4, 0.9 Hz, 1H), 6.59 – 6.44 (m, 1H), 6.13 (dt, J = 15.4,

7.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.01 (d, J = 7.8 Hz, 2H), 1.90 (d, J = 1.3 Hz, 3H),

1.24 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.9, 136.0, 135.1, 129.6, 129.5,

60.8, 32.0, 14.3, 12.8.

Ethyl‐4,4-dimethoxy-3-methylbut-2-enoate (29).32 A mixture of 1,1-dimethoxyacetone

27 (5.91 g, 50 mmol) and ethyl 2-(diethoxyphosphoryl)acetate 28 (13.45 g,

60 mmol) was added dropwise to a suspension of K2CO

3 (17.28 g) in 10

mL of water at room temperature. The reaction mixture was stirred for 16 h.

The insoluble material was then removed by filtration and washed with

OHEtO

O

BrEtO

O

OMe

OMe

O

OEt

Chapter 4

85

ether. The organic phase was separated and washed with brine (50 mL). The organic layer

was dried over Na2SO4, filtered, concentrated and purified by flash chromatography

(eluent pentane/ether) to give product 29 as colorless oil (8.0 g, 85%, mixture of E and Z

acetal esters).

(2E,4E)- Ethyl -6- hydroxy-3- methylhexa- 2,4-dienoate (33).33 HCl (3 N, 3.5 mL

of an aq. solution) was added dropwise to a stirred solution of the

above obtained esters 29 (2.00 g, 10.6 mmol) in 15 mL DCM at

0 °C. The resulting mixture was stirred for 2 h. The organic layer

was separated and washed with a saturated aqueous solution of

NaHCO3 (30 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The

crude product was purified by vacuum distillation to yield the aldehyde 30 which was

used directly for the next step.

Compound 31 (3.20 g, 10.6 mmol) was added to a stirred solution of the aldehyde 30 in

DCM (10 mL) at room temperature. The reaction mixture was stirred for 15 h and

subsequently concentrated. The resulting mixture was dissolved in pentane and the solids

were filtered. The solution was concentrated to give the crude aldehyde 32 which was

used in the next step.

A solution of the aldehyde 32 in 5 mL of ethanol was added to a solution of sodium

borohydride (1.0 g, 25 mmol) in EtOH/H2O (1:1, 20 mL) at 0 °C. The reaction mixture

was stirred at room temperature for 20 min followed by quenching with aqueous

saturated NaCl. The aqueous layer was separated and extracted with Et2O (5 x 20 mL).

The combined organic layers were dried over Na2SO4, filtered, concentrated and purified

by flash chromatography (eluent pentane/ether = 1/1) to give product 33 as colorless oil

(0.87 g, 50% yield over three steps). 1H NMR (400 MHz, CDCl3) δ 6.26 (d, J = 15.8

Hz, 1H), 6.17 (m, 1H), 5.71 (s, 1H), 4.24 (d, J = 5.2 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H),

2.22 (s, 3H), 1.51 (br, 1H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.0,

151.3, 134.3, 133.8, 119.7, 63.1, 59.8, 14.3, 13.8.

(2E,4E)-Ethyl-6-bromo-3-methylhexa-2,4-dienoate (1f). To a stirred solution of NBS

(470 mg, 2.64 mmol, 1.3 eq) in DCM (20 mL) at –20 oC was slowly

added Me2S (197 mg, 0.23 mL, 3.17 mmol, 1.83 eq) over a 5 min

period. The reaction mixture was stirred for 15 min before a solution

of allylic alcohol 33 (300 mg, 1.76 mmol) in 5 mL of DCM was

added dropwise over 10 min. The mixture was quenched with a saturated aqueous NH4Cl

solution (50 mL) when TLC showed full conversion and subsequently the mixture was

warmed up to room temperature and the layers were separated. The organic layer was

OEtO

OH

OEtO

Br

Chapter 4

86

washed with water (3 x 10 mL), dried over Na2SO4, filtered and concentrated to give

crude 1f as colorless oil (354 mg, 86%) used in the next step immediately due to

instability. 1H NMR (400 MHz, CDCl3) δ 6.29 – 6.13 (m, 2H), 5.73 (s, 1H), 4.11 (q, J =

7.1 Hz, 2H), 3.99 (d, J = 7.1 Hz, 2H), 2.20 (d, J = 1.2 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.6, 150.3, 137.6, 130.7, 121.1, 59.9, 32.0, 14.3, 13.8.

(Z)-Ethyl-3-iodobut-2-enoate (35).34 To a mixture of ethyl but-2-ynoate 34 (2.34 g, 20

mmol) and lithium iodide (4.4 g, 32 mmol, 1.6 eq) was added acetic acid

(6 mL) at room temperature. The reaction mixture was heated to 70 oC

and stirred for 16 h followed by dilution with ether (50 mL). The organic phase was

washed with water (20 mL), saturated aqueous NaHCO3 (20 mL), and saturated aqueous

Na2S2O3 (20 mL), dried over Na2SO4, filtered and concentrated and purified by flash

chromatography (eluent pentane/ether = 10/1) to give product 35 as a colorless oil (2.1 g,

88% yield). 1H NMR (400 MHz, CDCl3) δ 6.29 (q, J = 1.4 Hz, 1H), 4.22 (q, J = 7.1 Hz,

2H), 2.73 (d, J = 1.4 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H).

(2Z,4E)-Ethyl‐6-hydroxy-3-methylhexa-2,4-dienoate (37). A solution of Pd2(dba)3 (45

mg, 0.005 mmol) in 20 mL of NMP was treated with triphenyl

arsine (59 mg, 0.2 mmol) at room temperature. The solution was

stirred for 10 min followed by the addition of a solution of iodide 35

(466 mg, 1.94 mmol) in 5 mL of NMP. The solution was further

stirred for 10 min followed by the addition of a solution of stannane 3613 (674 mg, 1.94

mmol) in 5 mL of NMP. The reaction mixture was stirred for 16 h followed by quenching

with saturated aqueous potassium fluoride solution (20 mL). The reaction mixture was

diluted with diethyl ether (20 mL). The organic layer was separated and washed with

saturated aqueous potassium fluoride solution (10 mL), dried over Na2SO4, filtered and

concentrated. The product was purified by column chromatography (eluent pentane/ether

= 2/1) to give 37 as a colourless oil (252 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.75

(dd, J = 16.0, 0.7 Hz, 1H), 6.23 (dt, J = 16.0, 5.6 Hz, 1H), 5.71 (s, 1H), 4.32 (td, J = 5.6,

1.4 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 2.02 (d, J = 1.3 Hz, 3H), 1.63 (br, 1H), 1.28 (t, J =

7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.2, 150.0, 135.8, 127.8, 117.9, 63.6, 59.8,

21.0, 14.3. HRMS (APCI+) calculated for C9H13O2[M–OH]+:153.0910, found:153.0909.

I O

OEt

O

OEt

HO

Chapter 4

87

(2Z,4E)-Ethyl-6-bromo-3-methylhexa-2,4-dienoate (1g). To a stirred solution of NBS

(313 mg, 1.76 mmol, 1.3 eq) in DCM (20 mL) at –20 oC was slowly

added Me2S (132 mg, 0.16 mL, 2.12 mmol, 1.83 eq) over a 5 min

period. The reaction mixture was stirred for 15 min before a solution

of allylic alcohol 37 (200 mg, 1.18 mmol) in 5 mL of DCM was

added dropwise over 10 min. The mixture was quenched with a saturated aqueous NH4Cl

solution (50 mL) after TLC showed full conversion and subsequently the mixture was

warmed up to room temperature and the layers were separated. The organic layer was

washed with water (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated

to give the crude 1g as colorless oil (214 mg, 78%) used in the next step immediately due

to instability. 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 15.6, 0.9 Hz, 1H), 6.23 (dt, J =

15.6, 7.8 Hz, 1H), 5.72 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.10 (dd, J = 7.8, 0.9 Hz, 2H),

2.00 (d, J = 1.3 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.9,

149.0, 132.0, 131.1, 119.2, 59.9, 32.6, 20.8, 14.3.

(E)-3-Iodo-2-methylprop-2-en-1-ol (42):35 To a flame-dried, nitrogen-purged round

bottom flask (500 mL) was added dry DCM (100 mL) and Cp2ZrCl2 (3.78

g, 12.9 mmol). The above solution was cooled to 0°C and Me3Al (2 M in

toluene, 77.6 mL, 155 mmol) was added dropwise followed by addition of a solution of

propargyl alcohol 38 (3 mL, 51.5 mmol) in 10 mL of DCM. The mixture was warmed up

to room temperature and stirred overnight. The solution was cooled to -30 °C and I2 (19.6

g, 77.3 mmol) was added. After 3 h stirring at room temperature, the solution was

quenched by sat. potassium sodium tartrate to give a heterogeneous solution. The mixture

was filtered through celite and filter cake was further rinsed with ether. The aqueous

layer was washed with DCM (3 x 50 mL) and the combined organic layers were washed

with brine, dried over anhydrous MgSO4, filtered, and concentrated via rotary

evaporation to give crude product 42 which was used directly for the next step.

(E)-tert-Butyl(3-iodo-2-methylallyloxy)dimethylsilane (43):35 The mixture 42 obtained

from above step was dissolved in dry DCM (100 mL) followed by the

addition of TBSCl (3.60 g, 24.5 mmol) and imidazole (1.70 g, 24.5

mmol). The solution was stirred at room temperature for 3 h and quenched with 30 mL of

water and extracted with ether (3 x 30 mL). The combined organic layers were dried over


pentane/ether) to give 43 as colorless oil (3.49 g, 78% yield). 1H NMR (400 MHz, CDCl3)

δ 6.13 (dd, J = 2.6, 1.3 Hz, 1H), 4.03 (d, J = 1.0 Hz, 2H), 1.71 (d, J = 0.6 Hz, 3H), 0.84 (s,

9H), 0.00 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 146.8, 75.9, 67.1, 25.8, 21.1, 18.3, -5.5.

O

OEt

Br

OHI

OTBSI

Chapter 4

88

(E)-Methyl-3-(tributylstannyl)acrylate (41):18 To a stirred solution of n-butyllithium

(43 mL, 1.6 M solution in hexanes, 68.7 mmol) in 50 mL of dry

THF was added dropwise bistributyltin (34.7 mL, 68.7 mmol) at 0 oC under nitrogen. The solution was stirred for 20 min before

transferred by cannula to a precooled solution of copper bromide dimethylsulfide

complex (14.2 g, 68.9 mmol) in 30 mL of dry THF at -50 oC. The resulting black mixture

was stirred for 25 min before cooling to -78 oC. A THF solution of methyl propiolate (2.0

mL, 22.9 mmol) was added dropwise and the reaction mixture was stirred for 4 h. Dry

methanol (69 mL) was added and the reaction was warmed to room temperature. The

reaction mixture was partitioned between diethyl ether (100 mL) and water (100 mL) and

filtered through Celite to remove the dark coloration. The phases were separated and the

aqueous fraction was extracted with ether (3 x 50 mL). The combined organic layers

were washed with brine (150 mL), dried over MgSO4, and concentrated. The product was

purified by column chromatography (eluent pentane/ether) to afford stannane 41 as

colorless oil (9.9 g, quant. yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 19.4 Hz,

1H), 6.24 (d, J = 19.4 Hz, 1H), 3.68 (s, 3H), 1.44 (dd, J = 12.0, 4.4 Hz, 6H), 1.23 (dt, J =

14.1, 7.1 Hz, 6H), 0.96 – 0.86 (m, 6H), 0.83 (td, J = 7.3, 4.5 Hz, 9H).

(2E,4E)-Methyl-6-(tert-butyldimethylsilyloxy)-5-methylhexa-2,4-dienoate (44): A

solution of Pd2-(dba)3 (157 mg, 0.17 mmol) in 50 mL of

NMP was treated with triphenyl arsine (105 mg, 0.34 mmol)

at room temperature. The solution was stirred for 10 min

followed by the addition of a solution of iodide 43 (1.20 g, 3.77 mmol) in 5 mL of NMP.

The solution was further stirred for 10 min followed by the addition of a solution of

stannane 41 (1.29 g, 3.43 mmol) in 5 mL of NMP. The reaction mixture was stirred

overnight followed by quenching with saturated aqueous potassium fluoride solution (30

mL). The reaction was diluted with diethyl ether (30 mL). The organic layer was

separated and washed with saturated aqueous potassium fluoride solution (10 mL), dried

and concentrated. The product was purified by column chromatography (eluent

pentane/ether) to give 44 as colorless oil (750 mg, 81%). 1H NMR (400 MHz, CDCl3) δ

7.53 (dd, J = 15.2, 11.8 Hz, 1H), 6.19 (dd, J = 11.8, 0.8 Hz, 1H), 5.78 (d, J = 15.2 Hz,

1H), 4.05 (d, J = 0.6 Hz, 2H), 3.67 (s, 3H), 1.75 (d, J = 0.7 Hz, 3H), 0.84 (s, 9H), 0.00 (s,

6H); 13C NMR (101 MHz, CDCl3) δ 167.9, 147.7, 140.5, 120.9, 119.7, 67.3, 51.4, 25.9,

18.4, 14.4, -5.4. HRMS (APCI+) calculated for C14H27O3Si:271.1724, found:271.1718.

MeO

O

OTBS

Chapter 4

89

(2E,4E)-6-(tert-Butyldimethylsilyloxy)-5-methylhexa-2,4-dien-1-ol (45): To a stirred

solution of the methyl ester 44 (1.0 g, 3.7 mmol, 1 equiv.) in

30 mL of DCM was added DIBAL-H (2 ml, 1.60 g, 11.1

mmol, 3 equiv.) over 0.5 h at -78 oC under nitrogen. The

reaction mixture was stirred for about 4 h when TLC showed full conversion. The

reaction mixture was quenched with 30 mL saturated aqueous Rochelle salt (potassium

sodium tartrate) and stirred for 30 min. The phases were separated and the aqueous layer

was extracted with DCM (3 x 30 mL). The combined organic phases were dried over

Na2SO4, concentrated and purified by flash chromatography (eluent pentane/ether) to

give 45 as colorless oil (720 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 6.43 (ddt, J

= 15.0, 11.0, 1.4 Hz, 1H), 6.02 (d, J = 11.1 Hz, 1H), 5.74 (dt, J = 15.1, 6.0 Hz, 1H), 4.14

(d, J = 6.0 Hz, 2H), 4.00 (s, 2H), 1.66 (s, 3H), 1.37 (d, J = 5.2 Hz, 1H), 0.85 (s, 9H), 0.00

(s, 6H); 13C NMR (101 MHz, CDCl3) δ 138.1, 130.9, 127.5, 122.5, 67.9, 63.7, 25.9, 18.4,

13.9, -5.4. HRMS (APCI+) calculated for C13H25O3Si[M-OH]+:225.1669,

found:225.1667.

(But-2-ynyloxy)(tert-butyl)dimethylsilane (46):36 To a stirred solution of but-2-yn-1-ol

(930 mg, 13.3 mmol, 1 equiv.) in anhydrous dichloromethane (50 mL) was

added imidazole (1.00 g, 14.6 mmol, 1.1 equiv.) followed by

tert-butyl-dimethylsilyl chloride (2.2 g, 14.6 mmol, 1.1 equiv.), and the

resulting white suspension was stirred at room temperature for overnight. The reaction

mixture was quenched with 30 mL of water and extracted with ether (3 x 20 mL). The


flash chromatography (eluent pentane/EtOAc) to give 46 as colorless oil (2.32 g, 95%

yield). 1H NMR (400 MHz, CDCl3) δ 4.16 (d, J = 2.3 Hz, 2H), 1.72 (s, 3H), 0.80 (s, 9H),

0.00 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 80.9, 77.8, 52.0, 25.9, 18.4, 3.6, -5.2.

(E)-tert-Butyl(3-iodobut-2-enyloxy)dimethylsilane (48):20 To a stirred solution of

ZrCp2Cl2 (4.4 g, 15 mmol) in dry THF (50 mL) was added slowly

iBu2AlH (2.13 g, 2.73 mL, 15 mmol) at 0 oC under nitrogen. The

resultant suspension was stirred for 30 min at 0 oC, followed by addition of a THF

solution of alkyne 46 (850 mg, 4.61 mmol). The mixture was warmed to room

temperature and stirred until a homogeneous solution resulted (about 2 h) and then

cooled to –78 oC, followed by the addition of a THF solution of I2 (3.81 g, 15 mmol).

After stirring for 30 min, the reaction mixture was quenched with 1N HCl, extracted with

ether, washed successively with saturated Na2S2O3, NaHCO3 and brine, dried over

MgSO4, filtered, and concentrated. Flash chromatography (eluent, hexanes) to give 48 as

HOOTBS

OTBS

ITBSO

Chapter 4

90

colorless oil (0.84 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ 6.33 – 6.11 (m, 1H), 4.05

(d, J = 6.5 Hz, 2H), 2.34 (s, 3H), 0.83 (d, J = 1.1 Hz, 9H), 0.00 (d, J = 1.1 Hz, 6H); 13C

NMR (101 MHz, CDCl3) δ 140.6, 95.9, 60.7, 28.1, 25.9, 18.4, -5.2.

(2E,4E)-Methyl 6-(tert-butyldimethylsilyloxy)-4-methylhexa-2,4-dienoate (50): A

solution of Pd2-(dba)3 (60 mg, 0.066 mmol) in 50 mL of

NMP was treated with triphenyl arsine (67 mg, 0.22 mmol)

at room temperature. The solution was stirred for 10 min

followed by the addition of a solution of iodide 48 (0.840 g, 2.19 mmol) in 5 mL of NMP.

The solution was further stirred for 10 min followed by the addition of a solution of

stannane 41 (0.83 g, 2.2 mmol) in 5 mL of NMP. The reaction was stirred for overnight

followed by quenching with saturated aqueous potassium fluoride solution (30 mL). The

reaction was diluted with diethyl ether (30 mL). The organic layer was separated and

washed with saturated aqueous potassium fluoride solution (10 mL), dried and

concentrated. The product was purified by column chromatography (eluent pentane/ether)

to give 50 as colorless oil (607 mg, quant. yield). 1H NMR (400 MHz, CDCl3) δ 7.24 (d,

J = 15.5 Hz, 1H), 5.88 (dd, J = 6.3, 5.7 Hz, 1H), 5.77 (d, J = 15.7 Hz, 1H), 4.29 (d, J =

6.0 Hz, 2H), 3.68 (s, 3H), 1.69 (d, J = 1.0 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H); 13C NMR

(101 MHz, CDCl3) δ 167.7, 148.8, 140.5, 132.4, 116.6, 60.4, 51.5, 25.9, 18.3, 12.4, -5.2.

HRMS (APCI+) calculated for C14H27O3Si:271.1724, found:271.1722.

(2E,4E)-6-(tert-Butyldimethylsilyloxy)-4-methylhexa-2,4-dien-1-ol (51): To a stirred

solution of the methyl ester 50 (0.900 g, 3.33 mmol, 1 equiv.)

in 30 mL of DCM was added DIBAL-H (1.8 ml, 1.42 g, 9.98

mmol, 3 equiv.) over 0.5 h at -78 oC. The reaction mixture

was stirred for about 4 h when TLC showed full conversion. The reaction mixture was

quenched with 30 mL saturated aqueous Rochelle salt (potassium sodium tartrate) and

stirred for 30 min. The phases were separated and the aqueous layer was extracted with

DCM (3 x 30 mL). The combined organic phases were dried over Na2SO4, concentrated

and purified by flash chromatography (eluent pentane/ether) to give 51 as colorless oil

(647 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 6.19 (d, J = 15.7 Hz, 1H), 5.72 (dt, J

= 15.7, 6.0 Hz, 1H), 5.52 (t, J = 6.3 Hz, 1H), 4.25 (d, J = 6.3 Hz, 2H), 4.14 (dd, J = 6.0,

0.8 Hz, 2H), 1.68 (d, J = 0.9 Hz, 3H), 1.39 (br, 1H), 0.83 (s, 9H), 0.00 (s, 6H); 13C NMR

(101 MHz, CDCl3) δ 135.8, 133.3, 132.1, 126.9, 63.8, 60.2, 25.9, 18.4, 12.7, -5.1. HRMS

(APCI+) calculated for C9H17O2Si [M-tBu]+: 185.0998, found:185.1322.

MeO

O

OTBS

HOOTBS

Chapter 4

91

General procedure for the copper-catalyzed allylic alkylation of an allylic bromide

with organomagnesium reagents

A Schlenk tube equipped with septum and stirring bar was charged with CuBr•SMe2

(0.0125 mmol, 2.6 mg, 5 mol%) and the appropriate ligand (0.015 mmol, 6 mol%). Dry

dichloromethane (3 mL) was added and the solution was stirred under nitrogen at room

temperature for 15 min and cooled to –80 °C. Then, the corresponding organomagnesium

reagent (0.3 mmol, 1.2 eq) was added under nitrogen. Allylic bromide (0.25 mmol) was

dissolved in 1 mL of DCM and added dropwise to the reaction mixture over 1 h using a

syringe pump. The reaction was quenched after overnight with a saturated aqueous

NH4Cl solution (2 mL) and the mixture was warmed up to room temperature, diluted

with ether and the layers were separated. The aqueous layer was extracted with

dichloromethane (3 x 5 mL) and the combined organic layers were dried over anhydrous

Na2SO4, filtered and carefully concentrated (note: several products are highly volatile).

The crude product was purified by flash chromatography on silica gel using different

mixtures of n-pentane: Et2O as the eluent.

Note: Gas chromatography analysis was carried out to determine the SN2’:SN2 ratio’s and

ee’s on a sample obtained after aqueous extraction with dichloromethane, which has been

passed through a short plug of silica gel to remove transition metal residues.

(R,E)-(3-Methylpenta-1,4-dienyl)benzene (2a): The title compound was prepared from

1a (55 mg, 0.25 mmol) following the general procedure for the

copper-catalyzed asymmetric allylic alkylation. Purification by

column chromatography (SiO2, Pentane) afforded product (26 mg,

66% yield, 99% ee) as a colourless oil as a mixture of two regioisomers 2a/3a (SN2’/SN2)

in 95:5 ratio (determined by 1H NMR at 20 °C and GC). 1H NMR (400 MHz, CDCl3) δ

7.40 – 7.14 (m, 5H), 6.39 (d, J = 16.0 Hz, 1H), 6.18 (dd, J = 16.0, 7.0 Hz, 1H), 5.88 (ddd,

J = 17.0, 10.3, 6.5 Hz, 1H), 5.05 (m, 2H), 3.11 – 2.99 (m, 1H), 1.21 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 142.4, 137.6, 134.3, 128.6, 128.5, 127.0, 126.1, 113.3,

40.6, 19.8. HRMS (APCI+) calculated for C12H15:159.1168, found: 159.1157. [α]D20 =

–56.5 (c = 2.3, CHCl3), [Lit. 13 (S isomer, er = 96:4) [α]D20 = +55 (c = 0.87, CHCl3)].

Enantiomeric excess was determined by chiral GC analysis, CP-Chiralsil-Dex-CB (25 m

x 0.25 mm), initial temperature 80 ºC for 80 min, then 1oC/min to 140oC (hold for 5 min),

then 10oC/min to 180oC (final temp), retention times (min.): 25.8 (major) and 26.9

(minor); retention time 3a: 72.0 min.

In analogy to this result, the absolute configuration of the other products is assumed to be

(R).

Chapter 4

92

(R,E)-3,7-Dimethylocta-1,4-diene (2b): The title compound was prepared from 1b (50

mg, 0.25 mmol) following the general procedure for the


column chromatography (SiO2, Pentane) afforded product (11 mg, 32% yield, 99% ee) as

a colourless oil as a mixture of two regioisomers 2b/3b (SN2’/SN2) in 96:4 ratio

(determined by 1H NMR at 20 °C and GC). 1H NMR (400 MHz, CDCl3) δ 5.80 – 5.66 (m,

1H), 5.38 – 5.23 (m, 2H), 4.97 – 4.81 (m, 2H), 2.77 – 2.73 (m, 1H), 1.82 (dd, J = 9.7, 3.6

Hz, 2H), 1.55 – 1.50 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.80 (d, J = 6.6 Hz, 6H); 13C

NMR (101 MHz, CDCl3) δ 143.4, 135.0, 128.0, 112.4, 41.9, 40.3, 28.4, 22.2, 20.0.

HRMS (APCI+) calculated for C7H11 [M–iso-propyl]+: 95.0861, found: 95.0814. [α]D20 =

+4.8 (c = 0.25, CHCl3). Enantiomeric excess was determined by chiral GC analysis,

CP-Chiralsil-Dex-CB (25 m x 0.25 mm), initial temperature 60 ºC for 20 min, then

0.5oC/min to 100oC (hold for 10 min), then 1oC/min to 140oC (final temp), retention times

(min.): 15.1 (major) and 15.5 (minor); retention time 3b: 34.6 min.

(R,E)-Methyl-4-methylhexa-2,5-dienoate (2c):37 The title compound was prepared from

1c (51 mg, 0.25 mmol) following the general procedure for the


column chromatography (SiO2, Pentane/Et2O = 10/1) afforded

product (15 mg, 43% yield, 97% ee) as a colorless oil as a mixture of two regioisomers

2c/3c (SN2’/SN2) in 94:6 ratio (determined by 1H NMR at 20 °C and GC). 1H NMR (400

MHz, CDCl3) δ 6.86 (dd, J = 15.7, 6.9 Hz, 1H), 5.79 – 5.63 (m, 2H), 5.05 – 4.94 (m, 2H),

3.66 (s, 3H), 3.02 – 2.87 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3)

δ 167.1, 152.1, 140.0, 119.7, 114.8, 51.4, 40.0, 18.8. [α]D20 = –20 (c = 0.65, CHCl3).


x 0.25 mm), initial temperature 60 ºC for 20 min, then 0.5oC/min to 100oC (hold for 10

min), then 1oC/min to 140oC (final temp), retention times (min.): 35.9 (major) and 37.6

(minor); retention time 3c: 64.0 min.

(R,E)-tert-Butyldimethyl(4-methylhexa-2,5-dienyloxy)silane (2d): The title compound

was prepared from 1d (73 mg, 0.25 mmol) following the general

procedure for the copper-catalyzed asymmetric allylic alkylation.

Purification by column chromatography (SiO2, Pentane/Et2O = 10/1) afforded product

(52 mg, 92% yield, 99% ee) as a colorless oil as a mixture of two regioisomers 2d/3d

(SN2’/SN2) in 91:9 ratio (determined by 1H NMR at 20 °C and GC). 1H NMR (400 MHz,

CDCl3) δ 5.72 (ddd, J = 17.1, 10.3, 6.6 Hz, 1H), 5.58 – 5.39 (m, 2H), 4.91 (m, 2H), 4.08

O

O

TBSO

Chapter 4

93

(dt, J = 4.7, 1.0 Hz, 2H), 2.87 – 2.72 (m, 1H), 1.03 (d, J = 6.9 Hz, 3H), 0.84 (s, 9H), 0.00

(s, 6H); 13C NMR (101 MHz, CDCl3) δ 142.6, 134.5, 128.2, 112.9, 64.0, 39.9, 26.0, 19.6,

18.4, –5.1. HRMS (ESI+) calculated for C13H27OSi:227.1826, found: 227.1820. [α]D20 =

–4.4 (c = 2.5, CHCl3). Enantiomeric excess was determined by chiral GC analysis,

CP-Chiralsil-Dex-CB (25 m x 0.25 mm), initial temperature 80 ºC for 80 min, then

1oC/min to 140oC (hold for 5 min), then 10oC/min to 180oC (final temp), retention times

(min.): 23.6 (major) and 24.4 (minor); retention time 3d: 48.2 min.

(R,E)-Ethyl‐2,4-dimethylhexa-2,5-dienoate (2e): The title compound was prepared

from 1e (58 mg, 0.25 mmol) following the general procedure for

the copper-catalyzed asymmetric allylic alkylation. Purification by



2e/3e (SN2’/SN2) in 97:3 ratio (determined by 1H NMR at 20 °C and GC). 1H NMR (400

MHz, CDCl3) δ 6.51 (dd, J = 9.6, 1.4 Hz, 1H), 5.69 (ddd, J = 16.6, 10.3, 6.4 Hz, 1H),

5.02 – 4.87 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.16 – 3.10 (m, 1H), 1.79 (d, J = 1.3 Hz,

3H), 1.23 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ

168.3, 144.5, 140.6, 127.0, 113.7, 60.5, 37.0, 19.7, 14.3, 12.4. HRMS (APCI+) calculated

for C10H17O2:169.1223, found: 169.1219. [α]D20 = –2.8 (c = 1.85, CHCl3). Enantiomeric

excess was determined by chiral GC analysis, CP-Chiralsil-Dex-CB (25 m x 0.25 mm),

initial temperature 60 ºC for 20 min, then 0.5oC/min to 100oC (hold for 10 min), then

1oC/min to 140oC (final temp), retention times (min.): 54.6 (major) and 55.8 (minor);

retention time 3e: 86.3 min.

(R,E)-Ethyl-3,4-dimethylhexa-2,5-dienoate (2f): The title compound was prepared

from 1f (58 mg, 0.25 mmol) following the general procedure for

the copper-catalyzed asymmetric allylic alkylation. Purification by



2f/3f (SN2’/SN2) in 95:5 ratio (determined by 1H NMR at 20 °C and GC). 1H NMR (400

MHz, CDCl3) δ 5.75 – 5.60 (m, 2H), 5.05 – 4.96 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.89 –

2.77 (m, 1H), 2.05 (d, J = 1.3 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.0, 162.2, 140.3, 115.2, 115.0, 59.6, 47.2, 17.8, 16.8,

14.3. HRMS (APCI+) calculated for C10H17O2:169.1223, found: 169.1220. [α]D20 = +19.0

(c = 0.6, CHCl3). Enantiomeric excess was determined by HPLC analysis (Chiralpak

OD-H: 0.5 mL/min, n-heptane, 40 °C isotherm, 214 nm), retention times: 54.2 min

(major), 57.9 min (minor).

O

O

O

O

Chapter 4

94

(R,Z)-Ethyl‐3,4-dimethylhexa-2,5-dienoate (2g): The title compound was prepared

from 1g (58 mg, 0.25 mmol) following the general procedure for the



product (32 mg, 74% yield with trace of ether, 99% ee) as a colorless oil as a mixture of

two regioisomers 2g/3g (SN2’/SN2) in 96:4 ratio (determined by 1H NMR at 20 °C and

GC). 1H NMR (400 MHz, CDCl3) δ 5.77 (ddd, J = 16.4, 10.4, 6.0 Hz, 1H), 5.58 (s, 1H),

5.10 – 4.92 (m, 2H), 4.63 – 4.50 (m, 1H), 4.08 (q, J = 7.1 Hz, 2H), 1.71 (d, J = 1.0 Hz,

3H), 1.21 (t, J = 7.1 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ

166.1, 162.0, 140.4, 116.1, 114.3, 59.5, 37.9, 20.0, 17.1, 14.3. HRMS (APCI+) calculated

for C10H17O2:169.1223, found: 169.1222. [α]D20 = +130.1 (c = 1.5, CH2Cl2).


x 0.25 mm), initial temperature 60 ºC for 20 min, then 0.5oC/min to 100 oC (hold for 10

min), then 1 oC/min to 140 oC (final temp), retention times (min): 56.1 (major) and 56.5

(minor); retention time 3g: 80.6 min.

Cross metathesis between 2d and 52.

(S,2E,5E)-Ethyl-7-((tert-butyldimethylsilyl)oxy)-4-methylhepta-2,5-dienoate (53):

To a stirred solution of compound 2d/3d (20 mg, 0.088 mmol, 91/9) in 4 mL of dry DCM

was added ethyl acrylate 52 (9 mg, 0.09 mmol) and Hoveyda–Grubbs second-generation

catalyst22 (0.6 mg, 0.00088 mmol, 1 mol%) under a nitrogen atmosphere at room

temperature. The reaction mixture was stirred for 2 d and the product was purified by

flash chromatography (pentane/Et2O = 10/1) to give 53 as a colorless oil (15 mg, 57%)

which was contaminated by trace of compound 54. 1H NMR (400 MHz, CDCl3) δ 6.84

(dd, J = 15.7, 6.9 Hz, 1H), 5.72 (dd, J = 15.7, 1.4 Hz, 1H), 5.55 – 5.44 (m, 2H), 4.14 –

4.07 (m, 4H), 2.99 – 2.94 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H), 0.84

(s, 9H), 0.00 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 166.8, 152.1, 132.0, 129.8, 119.9,

63.6, 60.2, 38.7, 26.0, 19.1, 18.4, 14.3, -5.2. HRMS (APCI+) calculated for

C16H31O3Si:299.2042, found: 299.2037. [α]D20 = +8.2 (c = 0.7, CH2Cl2).

O O

Chapter 4

95

4.7 References and notes

1. M. S. F. L. K. Jie, M. K. Pasha, M. S. K. Syed-Rahmatulla, Nat. Prod. Rep., 1997, 14,

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T. V. RajanBabu, J. Am. Chem. Soc., 2006, 128, 54–53; (c) C. R. Smith, T. V. RajanBabu,

Org. Lett.,2008, 10, 1657–1659.

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Minnaard and B. L. Feringa, Chem. Rev., 2008, 108, 2824; (b) A. Alexakis, J. E. Bäckvall, N.

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Alexakis, In Transition Metal Catalyzed Allylic Substitution in Organic Synthesis (Ed. U.

Kazmaier,) Springer-Verlag, Berlin, 2012, pp. 235–268.

11. M. A. Kacprzynski, A. H. Hoveyda, J. Am. Chem. Soc., 2004, 126, 10676–10681.

12. H. Li, A. Alexakis, Angew. Chem. Int. Ed., 2012, 51, 1055 –1058.

13. M. Magrez, Y. L. Guen, O. Baslé, C. Crévisy, M. Mauduit, Chem. Eur. J., 2013, 19,

1199–1203.

14. H. Oda, T. Kobayashi, M. Kosugi, T. Migita, Tetrahedron, 1995, 51, 695–702; G. Pattenden,

D. A. Stoker, Synlett, 2009, 11, 1800–1802.

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15. F. -Y. Yang, M. Shanmugasundaram, S. -Y. Chuang, P. -J. Ku, M. -Y. Wu, C.-H. Cheng, J.

Am. Chem. Soc., 2003, 125, 12576–12583.

16. A. Barbero, F. J. Pulido, Chem. Soc. Rev., 2005, 34, 913–920.

17. R. J. Payne, F. Peyrot, O. Kerbarh, A. D. Abell, C. Abell, ChemMedChem, 2007, 2,

1015–1029.

18. (a) E. Piers, J. M. Chong, Can. J. Chem., 1988, 66, 1425 – 1429. (b) E. Piers, J. M. Chong, H.

E. Morton, Tetrahedron, 1989, 45, 363 –380.

19. J. Schwartz, J. A. Labinger, Angew. Chem. Int. Ed., 2003, 15, 330–340.

20. Z. Huang, E. Negishi, Org. Lett., 2006, 8, 3675–3678.

21. For selected examples, see: (a) F. López, A.W. van Zijl, A. J. Minnaard, B. L. Feringa, Chem.

Commun., 2006, 4, 409–411; (b) K. Geurts, S. P. Fletcher, B. L. Feringa, J. Am. Chem. Soc.

2006, 128, 15572-15573; (c) M. Fañanás-Mastral, B. ter Horst, A. J. Minnaard , B. L. Feringa,

Chem. Commun., 2011, 47, 5843–5845; (d) M. Pérez, M. Fañanás-Mastral, P. H. Bos, A.

Rudolph, S. R. Harutyunyan, B. L. Feringa, Nature Chem., 2011, 3, 377–38.

22. (a) S. J. Connon, S. Blechert, Angew. Chem. Int. Ed., 2003, 42, 1900–1923; (b) A. H. Hoveyda,

A. R. Zhugralin, Nature, 2007, 450, 243–251; (c) C. Samojlowicz, M. Bieniek, K. Grela,

Chem. Rev. 2009, 109, 3708–3742; (d) G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 2010,

110, 1746–1787.

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24. T. den Hartog, S. R. Harutyunyan, D. Font, A. J. Minnaard, B. L. Feringa, Angew. Chem. Int.

Ed., 2008, 47, 398–401.

25. B. Narasimhan, V. Judge, R. Narang, R. Ohlan, S. Ohlan, Bioorg. Med. Chem. Lett., 2007, 17,

5836–5845.

26. L. Ferrié, D. Amans, S. Reymond, V. Bellosta, P. Capdevielle, J. Cossy, J. Organomet. Chem.,

2006, 691, 5456–5465.

27. L. Boisvert, F. Beaumier, C. Spino, Org. Lett., 2007, 9, 5361–5363.

28. V. Gudipati, D. P. Curran, Tetrahedron Lett., 2011, 52, 2254–2257.

29. S. B. Han, A. Hassan, I. S. Kim, M. J. Krische, J. Am. Chem. Soc., 2010, 132, 15559–15561.

30. L. Zhao, X. Lu, W. Xu, J. Org. Chem., 2005, 70, 4059–4063.

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32. Q. Y. Hu, P. D. Rege, E. J. Corey, J. Am. Chem. Soc., 2004, 126, 5984–5986.

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131, 11678–11679.

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Chapter 4

98

Chapter 5

99

Chapter 5

Towards a Total Synthesis and Structure

Elucidation of Phorbasin B

In this chapter an approach towards the catalytic asymmetric synthesis of Phorbasin B is

presented. The copper-catalyzed asymmetric allylic alkylation presented in chapter 4 is

the key strategic transformation in this synthesis.

Chapter 5

100

5.1 Introduction

The Phorbasins1 (Figure 1) are a class of structurally novel diterpenes isolated from a

southern Australian marine sponge (Phorbas sp.). For example, Phorbasin B and C were

isolated during scientific trawling operations in the Great Australian Bight, while

Phorbasin D-F were isolated during an investigation of anticancer agents from marine

organisms. Preliminary biological studies of Phorbasins B, C and E showed that they

displayed GI50 (growth inhibition) values against several cancer cell lines in the range of

5-15 μM.1c As no follow-up appeared in chemical biology, we felt that a concise

synthesis of Phorbasins, taking advantage of highly efficient and selective catalytic

methods and making these compounds and analogs more readily available could greatly

stimulate biological studies.

Figure 1. Representative Phorbasins.

5.2 Previous synthesis of Phorbasins

In 2009 the group of Micalizio2 reported the first and so far the only total synthesis of

Phorbasin C (ent). They employed a titanium-mediated reductive cross-coupling3 (Figure

2) of diol 1 with TMS-propyne 2. This reaction proceeds via a formal metallo-[3,3]

rearrangement involving intermediate 3 with exquisite selectivity. However, the

1,4-diene unit was prepared in a multiple step sequence. As a starting material the chiral

alcohol 4 was used which was synthesized from (S)-Roche ester.4 Oxidation of the

alcohol to the corresponding aldehyde followed by a stereoselective Julia-Kocienski

olefination to give E-alkene 5. Removal of the THP group to the free alcohol, followed

by oxidation to the aldehyde and Takai olefination gave the 1,4-diene unit 6. Compared

Chapter 5

101

with the methodology developed in chapter 4, this synthetic route is less efficient.

OH

HO Br1. 2,2-DMP,PTSA2. OsO4, NMO

3.Bu3SnH, AIBN

OO

HO

OH

TMS

Ti(OiPr)4

O

OH

Ti

TMS

Me(L)n

OMe

Me-O

OO

-O

M+

Me

TMS

TiO (L)n

H+ OO

HO

Me

TMS

1. VO(acac)2,TBHP2. (COCl)2,DMSO

3. CH2=PPh3

OO

Me

TMS

O

1. Pd(PPh3)4, AcOH

2. Ac2O

OO

Me

TMS

AcOOAc

1. NIS2. TFA

3. IBX4. Sc(OTf)2

HOO

Me

I

AcOOAc

THPO OH THPO

B

O

O

I

Phorbasin C(ent)

1

2

3

4 5 6

Figure 2. Total synthesis of Phorbasin C (ent).2

5.3 First retrosynthetic analysis of Phorbasin B

In 1994 the group of Narasaka5 reported the total synthesis of Paniculide A (Figure 3) via

a chiral TADDOL-titanium complex catalyzed asymmetric D-A reaction of vinyl borate 7

in high yield and ee. We also envisioned applying this asymmetric D-A reaction in the

synthesis of Phorbasin B. In our retrosynthetic analysis (Figure 4), Phorbasin B was

disconnected into right part 8 (the 1,4-diene unit) and left part 9 (the cyclohexenone unit).

The former (both of the enantiomers) can be provided by copper-catalyzed asymmetric

allylic alkylation of diene bromide as described in chapter 4. The left part, 9, in principle

could be prepared by the above mentioned catalytic asymmetric D-A reaction followed

by further functionalization (Riley oxidation6 and Baylis-Hillman reaction7).

Chapter 5

102

Figure 3. Total synthesis of Paniculide A involving an enantioselective D‐A reaction.

Figure 4. First retrosynthetic analysis of Phorbasin B.

5.4 Results and discussion

The first attempt (Figure 5) towards the synthesis of vinyl borate 7 started from the

preparation of acid chloride 13. However, all attempts (PCl5, oxalyl chloride and PCl3) to

prepare 13 gave complicated products.

OH

O

HNO

O

O

N O

O O

N O

O

BO

O12 15 7

14Cl

O

13

oxalyl chloride or

PCl3 or PCl5

Figure 5. First attempt towards vinyl borate 7.

The second attempt (Figure 6) started by the synthesis of vinyl iodide 16 from acid 12

Chapter 5

103

using aq. HI. Chlorination of 16 using oxalyl chloride in neat form (Cl-I exchange

happened when the reaction was carried out in solvent) followed by addition of the

oxazolidinone 14 resulted in the vinyl iodide 17 in 70% overall yield. However, all

attempts (I-Li exchange followed by the synthesis of boronate8 and palladium catalyzed

coupling with di-boronate9) towards the synthesis of 7 failed.

Figure 6. Second attempt towards vinyl borate 7.

Figure 7. Final synthesis of vinyl borate 7.

The third route started from propargyl alcohol 18. TMS-protection of the terminal

position of alkyne 18 was followed by oxidation to acid 20 using Jones reagent.10

Chlorination in neat form followed by the addition of oxazolidinone 14 resulted in the

desired product 21 in 72% yield together with a trace of deprotected product 15. Removal

of the silyl group using TBAF gave product 15 in high yield. Hydroboration of alkyne 15

using Ipc2BH resulted in intermediate 22 which was quenched with ethanol to form

boronate 23. Exchange of the ethoxy groups with 2,2-dimethylpropane-1,3-diol finished

Chapter 5

104

the synthesis and gave 7 in 67% yield.

However, the Diels-Alder reaction (Figure 8) of vinyl borate 7 and diene 11 (mixture of

E/Z isomers) catalyzed by TADDOL-titanium complex didn’t work. Employing pure

E-diene 11 gave similar results and starting materials were recovered.

Figure 8. Attempted D‐A reaction catalyzed by TADDOL‐titanium complex.

5.5 Second retrosynthesis of Phorbasin B

Figure 9. Second retrosynthetic analysis of Phorbasin B.

In our second retrosynthetic analysis (Figure 9), Phorbasin B was disconnected into right

part 8 (the 1,4-diene unit) and left part 9 as before. The former (both of the enantiomers)

was provided by copper-catalyzed asymmetric allylic alkylation of diene bromide

described in chapter 4. The left part, 9, might be prepared from 25 by a Baylis-Hillman

reaction. Compound 25 is anticipated to be accessible via cyclization11 of ketone 26.

Chapter 5

105


Figure 10. Second route towards Phorbasin B.

Figure 11. Zimmerman‐Traxler transition state of Evans aldol reaction.

The second synthesis of Phorbasin B started from the preparation of chiral oxazolidinone

30 from acid 27 via chlorination followed by acylated carbamate formation (Figure 10).

Evans aldol reaction12 (the preferred transition state is showing in Figure 11 where the

dipoles of the enolate and the carbonyl group are opposed, and there is the least number

of unfavored steric interactions13) of 30 with aldehyde 31 first resulted in borinate ester

32 which was initially oxidative cleaved by methanol and hydrogen peroxide. However

elimination product 33 was the only product. Employing neutral conditions14 (pH=7

phosphate buffer) the oxidative cleavage gave the desired product 34 in 97% yield.

Reduction of 34 using LiBH4 resulted in diol 35 in high yield.

To investigate the effect of the protecting group on the cyclization (see Figure 9), linear

Chapter 5

106

and cyclic protecting groups were employed. For the synthesis of a cyclic acetal (Figure

12), initial acetal formation using TsOH and benzaldehyde dimethyl acetal resulted in

elimination product 36. Fortunately changing to a weaker acid, PPTS,15 the desired cyclic

product 37 was obtained in high yield. Wacker oxidation16 of 37 gave ketone 38 which

was transformed to aldehyde 39 by ozonolysis in pure DCM.17

Figure 12. Synthesis of cyclic keto‐aldehyde 39.

The synthesis of the linear keto-aldehyde 42 (Figure 12) followed the same sequence as

for the cyclic analogue. Protection using TBSCl gave 40 followed by Wacker oxidation

to ketone 41. Finally ozonolysis of the olefin moiety in 41 resulted in the product 42.

Figure 13. Synthesis of linear keto‐aldehyde 42.

Initial cyclization of 39 using aq. NaOH18 (Table 1, entry 1) resulted in only 5% yield.

Employing a two step sequence via the formation of hemi-acetal using DBU (0.5 equiv.)

followed by the formation of mesylate and elimination gave the desired product in 24%

yield.19 The highest yield was obtained using K2CO3 in tBuOH,20 however, the reaction

was very unselective. Finally using DBU under dehydration condition21 resulted in 18%

yield of cyclohexenone 43. The attempted cyclization of 42 using various conditions

didn’t result in desired product 44. The control of conformation via cyclic acetal is very

crucial for the cyclization which is entropically favored.22

Chapter 5

107

Table 1. Cyclization of 39 and 42.

Entry Conditiona Yieldb Conditiona Yieldb

1 aq.NaOH 5% aq.NaOH ‐‐

2 1. DBU, DCM

2. MsCl, Et3N

24% 1. DBU, DCM

2. MsCl, Et3N

‐‐

3 K2CO3, tBuOH 37%c TsOH, benzene ‐‐

4 DBU, benzene 18%

aThe reaction was stopped after 16 h.

boverall yield based on alkene 38.

cunselective reaction.

Table 2. Investigating the amount of the base used and reaction time.

Entry Condition Yielda

1 1.DBU(0.5 equiv.), DCM, rt, 1d; 2. MsCl, Et3N, DCM 24%

2 1.DBU(0.5 equiv.), DCM, rt, 2d; 2. MsCl, Et3N, DCM 26%

3 1.DBU(1 equiv.), DCM, rt, 2d; 2. MsCl, Et3N, DCM 40% (full conv.)

aOverall yield based on alkene 38.

With the most promising conditions in hand (Table 1, entry 2), we investigated the effect

of the amount of the base used and reaction time. Extending the reaction time to two days

didn’t improve the yield (Table 2, entry 2). Fortunately by doubling the amount of the

base to 1 equiv., the reaction finished in 2 d and gave 40% overall yield. The

stereochemistry of the cyclohexenone 43 with two cis-oriented substituents was

confirmed by its 1H NMR spectrum, in which the coupling constant between 4-H and

5-H (Table 2) was 2.9 Hz in good accordance with data for analogous cis-disubstituted

cyclohexenones.23

Chapter 5

108

Initial α-hydroxylation24 (Figure 14) of 43 using oxirane 46 and NaHMDS (for enolate

formation) gave a complex mixture of products. Employing a two step sequence25 (Figure

15) via the formation of silyl enol ether 47 followed by oxidation gave also complex

products. We later found that compound 43 was not stable under these basic conditions.

Employing mild conditions26 (Et3N and TESOTf), the silyl enol ether 50 was obtained in

quantitative yield (Figure 16), no further attempts to prepare 51 was made due to time

constraints.

Figure 14. Attempted α‐Hydroxylation of 43.

Figure 15. Attempted α‐Hydroxylation of 43.

Figure 16. α‐Hydroxylation of 43.

5.7 Conclusion

Several attempts have been made to synthesize fragments 25 and 8 of Phorbasin B. So far

we have achieved the synthesis of the right part (the 1,4-diene unit) in a highly

enantioselective manner as described in chapter 4. For the left part, we have achieved the

synthesis of the cyclohexenone ring 43 by intramolecular cyclization after the failure of

Chapter 5

109

asymmetric D-A approach. The stereochemistry of 43 was controlled by Evans aldol

reaction. Further functionalization of the ring especially using a Baylis-Hillman reaction

of 51 and Zr-catalyzed methylalumination of the acetylene side chain in 54 are required

in the future to finish the fragment 55 (Figure 17). The final key step would be the cross

metathesis of 55 and 8 with precise control of E-geometry of the double bond.

Comparison of the spectra and optical rotation with the natural product could be

employed to deduce the absolute configuration of the methyl group even the absolute

stereochemistry of Phorbasin B.

Figure 17. Synthesis route towards Phorbasin B




and distilled prior to use. Column chromatography was performed on silica gel (Aldrich

60, 230-400 mesh) or on aluminium oxide (Merck, aluminium oxide 90 neutral activated).

TLC was performed on silica gel 60/Kieselguhr F254.








Chapter 5

110



g/100 mL).

(E)-3-Iodoacrylic acid (16):27 A mixture of propiolic acid 12 (22 g, 314 mmol) and aq.

HI (72 mL of a 57% w/w (7 M) aqueous solution, 503 mmol) was heated

in three Al-foil-wrapped Ace tubes at 95 oC overnight. The resulting

mixtures were cooled to ambient temperature. The pressure was released (careful!!!), and

the mixture was diluted with water (5 mL) and filtered under vacuum. Washing of the

suspended product with light petroleum (20 mL), followed by drying afforded the iodo

acid 16 (35.1 g, 60%) as large white needles. 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J =

14.8 Hz, 1H), 6.90 (d, J = 14.8 Hz, 1H).

(E)-3-(3-Iodoacryloyl)oxazolidin-2-one (17): To a stirred solution of acid 16 (100 mg,

0.51 mmol, 1 equiv) and a catalytic amount of DMF was slowly added

oxalyl chloride (0.05 mL, 0.61 mmol, 1.2 equiv) at 0 oC under

nitrogen. The reaction mixture was warmed to room temperature and

stirred for 1 h to form the acid chloride. To another flask, NaH (30 mg, 60% dispersed in

mineral oil, 0.72 mmol, 1.4 equiv) was added to a stirred solution of compound 14 (57

mg, 0.66 mmol, 1.3 equiv) in 10 mL of dry THF at 0 oC under nitrogen. The mixture was

stirred for 30 min followed by the slow addition of above acid chloride. The reaction

mixture was warmed to room temperature and quenched with a saturated aq. NH4Cl

solution (5 mL) when TLC showed full conversion. The layers were separated, the

aqueous layer was washed with ether (3 x 5 mL) and the organic layers were dried over

anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography (eluent

pentane/ether) to give 17 as a white solid (93 mg, 70% yield). 1H NMR (300 MHz,

CDCl3) δ 8.28 (d, J = 14.5 Hz, 1H), 8.12 (d, J = 14.5 Hz, 1H), 4.45 (t, J = 8.0 Hz, 2H),

4.05 (t, J = 8.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 162.8, 153.1, 134.8, 101.7, 62.2,

42.5. HRMS (ESI+) calculated for C6H6INO3Na:289.9285, found: 289.9282.

3-(Trimethylsilyl)prop-2-yn-1-ol (19):28 To a stirred solution of propargyl alcohol 18

(4.66 mL, 4.5 g, 80 mmol) in THF (100 mL) at –78 °C was added

dropwise n-BuLi (1.6 M in hexanes, 100 mL, 160 mmol, 200 mol %).

After stirring for 20 min at –78 °C, TMSCl (25 mL, 196 mmol, 220

mol %) was added dropwise. The reaction mixture was stirred for 5 min at –78 °C,

warmed to room temperature and stirred for an additional1 h. The reaction was quenched

with 50 mL water and then 10% aq. HCl was added to the crude reaction mixture until

OH

O

I

N

O

I O

O

OH

TMS

Chapter 5

111

complete consumption of the TMS-ether was observed according to TLC analysis. The

layers were separated, the aqueous layer was washed with ether (3 x 50 mL) and the

organic layers were dried over anhydrous Na2SO4, filtered, concentrated and the crude

product was purified by flash chromatography (eluent pentane/ether) to give 19 as

colorless oil (9.65 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 4.26 (d, J = 6.1 Hz, 2H),

1.76 (t, J = 5.3 Hz, 1H), 0.17 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 103.8, 90.6, 51.6,

-0.2.

3-(Trimethylsilyl)propiolic acid (20):29 Jones’ reagent (11.1 mL, 2.7 M) was added

dropwise to an ice-cold solution of alcohol 19 (1.14 g, 10 mmol) in

acetone (100 mL). The resulting mixture was stirred for 1 h at room

temperature. The mixture was diluted with tert-butyl methyl ether (50

mL) and washed with water; the organic phase was dried over Na2SO4, filtered,

concentrated and the residue was purified by flash chromatography (eluent pentane/ether)

to give 20 as colorless oil (1.24 g, 98% yield). 1H NMR (400 MHz, CDCl3) δ 10.30 (br,

1H), 0.26 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 157.2, 97.2, 93.8, -1.0.

3-(3-(Trimethylsilyl)propioloyl)oxazolidin-2-one (21): To a stirred solution of acid 20

(14.5 g, 100 mmol, 1 equiv) and a catalytic amount of DMF was

slowly added oxalyl chloride (9.5 mL, 110 mmol, 1.1 equiv) at 0 oC

under nitrogen. The reaction mixture was warmed to room

temperature and stirred for 1 h to form the acid chloride. To another flask, NaH (6.00 g,

60% dispersed in mineral oil, 150 mmol, 1.5 equiv) was added to a stirred solution of

compound 14 (13 g, 150 mmol, 1.5 equiv) in 100 mL of dry THF at 0 oC under nitrogen.

The mixture was stirred for 30 min followed by the slow addition of above acid chloride.

The reaction mixture was warmed to room temperature and quenched with a saturated aq.

NH4Cl solution (50 mL) after TLC showed full conversion, the layers were separated.

The aqueous layer was washed with ether (3 x 50 mL) and the organic layers were dried

over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography

(eluent pentane/ether) to give 21 as colorless oil (15.1 g, 72% yield). 1H NMR (400 MHz,

CDCl3) δ 4.44 – 4.36 (m, 2H), 4.06 – 3.95 (m, 2H), 0.29 – 0.23 (m, 9H); 13C NMR (101

MHz, CDCl3) δ 172.3, 150.2, 105.0, 94.1, 61.9, 42.3, -1.0. HRMS (ESI+) calculated for

C9H13NO3SiNa:234.0557, found: 234.0554.

OH

TMS

O

O

N O

O

TMS

Chapter 5

112

3-Propioloyloxazolidin-2-one (15):30 To a stirred solution of 21 (15.1 g, 72 mmol) in

THF (50 mL) was added TBAF (1.0 M solution in THF, 108 mL, 108

mmol) at room temperature. The resulting solution was stirred for 4 h,

and then quenched with sat. aq. NH4Cl and extracted with EtOAc (3 x 50

mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and the

crude product was purified by flash chromatography (eluent pentane/ether) to give 15 as

a colorless oil (7.75 g, 77%): 1H NMR (400 MHz, CDCl3) δ 4.46 (dd, J = 8.5, 7.5 Hz,

2H), 4.06 (dd, J = 8.5, 7.4 Hz, 2H), 3.45 (s, 1H).

Preparation of Ipc2BH: A 50-mL centrifuge vial fitted with a rubber septum and

magnetic stirring bar was charged with borane dimethylsulfide (2.58 mL, 25 mmol) and

25 mL of dry THF under nitrogen. The mixture was cooled to 0 oC and (+)-α-pinene

(7.94 mL, 50 mmol) was added dropwise with stirring. After the complete addition of

α-pinene, the stirring was stopped and the centrifuge vial was stored at 0 oC overnight.

The supernatant solution was decanted by using a double-ended needle. The crystalline

lumps of (-)-Ipc2BH were broken, washed with dry ether (3 x 10 mL) and dried at room

temperature to afford the product: 5.3 g (74% yield).

(E)-3-(3-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)acryloyl)oxazolidin-2-one (7):30

Under an argon atmosphere, 15 (2.10 g, 15.1 mmol) was

added to a THF (20 mL) suspension of

diisopinocampheylborane (6.10 g, 22.6 mmol) at 0 oC. After

stirring for 1.5 h, excess acetaldehyde (12.6 mL, 226 mmol)

was added and the mixture was warmed to 40 oC and stirred for 1 h. The mixture was

cooled to ambient temperature followed by the addition of 2,2-dimethyl- 1,3-propanediol

(2.34 g, 22.6 mmol) and subsequently stirred for 3 h. After removal of the solvent under

reduced pressure, ethanol was added to the residue. The resulting precipitates were

filtered, washed with ether and then dried to afford the product 7 (3.1 g, 82%) as a white

solid. 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 17.7 Hz, 1H), 6.89 (d, J = 17.7 Hz, 1H),

4.44 (t, J = 8.0 Hz, 2H), 4.08 (t, J = 8.0 Hz, 2H), 3.67 (s, 4H), 1.58 (s, 3H), 0.98 (s, 3H).

(R)-4-Benzyl-3-(pent-4-enoyl)oxazolidin-2-one (30): To a stirred solution of acid 27

(8.05 g, 80.4 mmol, 1.5 equiv) and a catalytic amount of DMF was

slowly added oxalyl chloride (10.2 g, 6.9 mL, 80.4 mmol, 1.5 equiv)

at 0 oC under nitrogen. The reaction mixture was warmed to room

temperature and stirred for 1 h to form acid chloride. To another flask,

NaH (2.80 g, 60% dispersed in mineral oil, 64.3 mmol, 1.2 equiv) was added to a stirred

O

N O

O

O

N O

O

BO

O

ON

O

Bn

O

Chapter 5

113

solution of compound 29 (9.50 g, 53.6 mmol, 1 equiv) in 100 mL of dry THF at 0 oC

under nitrogen. The mixture was stirred for 30 min followed by the slow addition of

above acid chloride. The reaction mixture was warmed to room temperature and

quenched with a saturated aq. NH4Cl solution (50 mL) when TLC showed full

conversion. The layers were separated, the aqueous layer was washed with ether (3 x 50

mL) and the organic layers were dried over anhydrous Na2SO4, filtered, concentrated and

the crude product was purified by flash chromatography (eluent pentane/ether) to give 30

as colorless oil (12.21 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.28 (ddd, J = 30.2,

19.3, 6.8 Hz, 5H), 5.88 (ddt, J = 16.9, 10.3, 6.5 Hz, 1H), 5.07 (ddd, J = 13.7, 11.5, 1.4 Hz,

2H), 4.67 (ddd, J = 10.5, 7.1, 3.5 Hz, 1H), 4.25 – 4.11 (m, 2H), 3.30 (dd, J = 13.4, 3.3 Hz,

1H), 3.06 (qt, J = 17.2, 7.3 Hz, 2H), 2.76 (dd, J = 13.4, 9.6 Hz, 1H), 2.54 – 2.37 (m, 2H); 13C NMR (101 MHz, CDCl3) δ172.5, 153.6, 136.7, 135.2, 129.4, 128.9, 127.3, 115.7,

66.2, 55.2, 37.9, 34.8, 28.2. HRMS (ESI+) calculated for C15H18O3N:260.1281, found:

260.1276. [α]D20 = -73.8 (c = 3.0, CHCl3).

(R)-3-((2R,3S)-2-Allyl-3-hydroxy-5-methylhex-4-enoyl)-4-benzyloxazolidin-2-one

(34): To a stirred solution of compound 30 (2.6 g, 10 mmol, 1 equiv) in 30 mL of dry

DCM was added dibutylboron triflate (11 mL, 1 M in DCM, 1.1

equiv) at 0 oC under nitrogen followed by

N,N-di-isopropylethylamine (2 mL, 1.55 g, 1.2 mmol, 1.2 equiv).

The resulting solution was stirred for 1 h at that temperature and

cooled to -78 oC. A DCM solution of aldehyde 31 (925 mg, 11

mmol, 1 equiv) was slowly added to the above solution, the mixture was warmed to room

temperature and stirred overnight. The reaction was quenched with 50 mL of phosphate

buffer (pH=7) followed by oxidative workup with aq. H2O2 (10 mL) in methanol. The


anhydrous Na2SO4, filtered, concentrated and the crude product was purified by flash

chromatography (eluent pentane/ether) to give 34 as colorless oil (3.33 g, 97% yield). 1H

NMR (400 MHz, CDCl3) δ 7.44 – 7.16 (m, 5H), 5.95 – 5.76 (m, 1H), 5.36 – 5.25 (m, 1H),

5.07 (ddd, J = 13.6, 11.0, 1.1 Hz, 2H), 4.80 – 4.59 (m, 2H), 4.38 – 4.21 (m, 1H), 4.21 –

4.09 (m, 2H), 3.28 (dd, J = 13.4, 3.3 Hz, 1H), 2.77 – 2.60 (m, 1H), 2.60 – 2.53 (m, 1H),

2.49 (ddd, J = 7.9, 6.1, 3.1 Hz, 1H), 1.74 (d, J = 1.1 Hz, 3H), 1.69 (d, J = 1.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 174.3, 153.7, 137.3, 135.3, 135.3, 129.4, 128.9, 127.3,

123.8, 117.2, 69.4, 66.0, 55.6, 47.8, 38.0, 32.7, 25.9, 18.4. HRMS (ESI+) calculated for

C20H24O3N:326.1751, found: 326.1745. [α]D20 = -38.6 (c = 0.15, CHCl3).

ON

O

Bn

OOH

Chapter 5

114

(2S,3S)-2-Allyl-5-methylhex-4-ene-1,3-diol (35): To a stirred solution of alcohol 34

(3.33 g, 9.7 mmol, 1 equiv) in MeOH/THF (40 mL, 1/1 v/v) was added

LiBH4 (423 mg, 19.4 mmol, 2 equiv) at 0 oC under nitrogen. The mixture

was warmed to room temperature and quenched with a saturated aq. NH4Cl

solution (30 mL) when TLC showed full conversion. The layers were

separated, the aqueous layer was washed with ether (3 x 30 mL) and the organic layers

were dried over anhydrous Na2SO4, filtered, concentrated and the crude product was

purified by flash chromatography (eluent pentane/ether) to give 35 as colorless oil (1.37 g,

83% yield). 1H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J = 17.3, 10.1, 7.0 Hz, 1H), 5.34 (d,

J = 9.2 Hz, 1H), 5.04 (t, J = 12.2 Hz, 2H), 4.56 (dd, J = 9.2, 4.3 Hz, 1H), 3.76 (dd, J =

10.9, 7.3 Hz, 1H), 3.66 (dd, J = 10.9, 4.1 Hz, 1H), 2.35 (s, 2H), 2.15 – 2.04 (m, 1H), 2.00

(dd, J = 14.3, 7.7 Hz, 1H), 1.95 – 1.86 (m, 1H), 1.76 (s, 3H), 1.68 (s, 3H); 13C NMR (101

MHz, CDCl3) δ 136.9, 136.6, 124.4, 116.4, 71.2, 63.9, 45.1, 31.4, 26.1, 18.4. HRMS

(ESI+) calculated for C10H18O2Na:193.1199, found: 193.1211. [α]D20 = -3.3 (c = 0.65,

CHCl3).

(2R,4S,5S)-5-Allyl-4-(2-methylprop-1-en-1-yl)-2-phenyl-1,3-dioxane (37): To a stirred

solution of diol 35 (1.17 g, 6.85 mmol, 1 equiv) in 30 mL of dry DCM

was added benzaldehyde dimethyl acetal (1.03 mL, 1.04 g, 6.85 mmol, 1

equiv) and PPTS (pyridinium p-toluenesulfonate, 86 mg, 0.34 mmol, 5

mol%) at room temperature. The resulting solution was stirred overnight

and quenched with excess triethylamine (10 mL) followed by a

saturated aq. NH4Cl solution (30 mL). The layers were separated, the aqueous layer was

washed with ether (3 x 20 mL) and the organic layers were dried over anhydrous Na2SO4,

filtered, concentrated and the crude product was purified by flash chromatography (eluent

pentane/ether) to give 37 as colorless oil (1.2 g, 68% yield). 1H NMR (400 MHz, CDCl3)

δ 7.60 – 7.27 (m, 5H), 5.94 – 5.75 (m, 1H), 5.61 (s, 1H), 5.38 (d, J = 7.7 Hz, 1H), 5.24 –

5.04 (m, 2H), 4.79 (dd, J = 7.7, 2.2 Hz, 1H), 4.25 (d, J = 11.4 Hz, 1H), 4.00 (d, J = 11.4

Hz, 1H), 2.73 – 2.53 (m, 1H), 2.49 – 2.35 (m, 1H), 1.77 (s, 3H), 1.73 (s, 3H), 1.49 (dd, J

= 10.7, 2.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 138.8, 137.3, 135.3, 128.8, 128.2,

126.3, 123.3, 116.7, 102.2, 76.7, 69.5, 38.1, 29.3, 25.9, 18.6. HRMS (ESI+) calculated

for C17H22O2Na:281.1512, found: 281.1508. [α]D20 = -8.0 (c = 0.65, CHCl3).

OHOH

Chapter 5

115

1-((2R,4S,5S)-4-(2-Methylprop-1-en-1-yl)-2-phenyl-1,3-dioxan-5-yl)propan-2-one

(38): To a stirred solution of alkene 37 (1.15 g, 4.45 mmol, 1 equiv) in DMA/H2O (30

mL, 1/1 v/v) was added palladium dichloride (79.0 mg, 0.445 mmol, 10

mol%) and Cu(OAc)2•H2O (178 mg, 0.89 mmol, 20 mol%) at room

temperature under 1 atmosphere of oxygen. The reaction mixture was

stirred for 2 d and quenched with a saturated aq. NH4Cl solution (50 mL)

after TLC showed full conversion. The layers were separated, the



chromatography (eluent pentane/ether) to give 38 as colorless oil (0.93 g, 76% yield). 1H

NMR (300 MHz, CDCl3) δ 7.57 – 7.29 (m, 5H), 5.58 (d, J = 3.0 Hz, 1H), 5.29 – 5.06 (m,

1H), 4.85 – 4.67 (m, 1H), 4.09 (d, J = 1.5 Hz, 2H), 3.06 (dt, J = 9.5, 6.3 Hz, 1H), 2.75

(dd, J = 18.6, 3.3 Hz, 1H), 2.19 (d, J = 3.1 Hz, 3H), 2.18 – 2.07 (m, 1H), 1.73 (s, 3H),

1.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 208.5, 138.7, 136.4, 129.1, 128.5, 126.3,

102.1, 80.4, 76.8, 71.2, 39.8, 33.8, 30.9, 26.1, 18.9. HRMS (ESI+) calculated for

C17H22O3Na:297.1461, found: 297.1457. [α]D20 = -6.0 (c = 0.2, CHCl3).

(2R,4R,5S)-5-(2-Oxopropyl)-2-phenyl-1,3-dioxane-4-carbaldehyde (39): To a stirred

solution of ketone 38 (521 mg, 1.9 mmol) in DCM was bubbled O3 at -78 oC. The ozonolysis was finished when the solution turned blue. Excess

dimethyl sulfide (5 mL) was added and the solution was warmed to room

temperature. The mixture was quenched with a saturated aq. NH4Cl

solution (20 mL). The layers were separated, the aqueous layer was washed

with ether (3 x 20 mL) and the organic layers were dried over anhydrous

Na2SO4, filtered, concentrated and the crude product was purified by flash

chromatography (eluent pentane/ether) to give 39 as colorless oil which was used

immediately for the next step. 1H NMR (300 MHz, CDCl3) δ 9.62 (s, 1H), 7.54 – 7.38 (m,

5H), 5.59 (s, 1H), 4.48 (d, J = 2.6 Hz, 1H), 4.12 (dd, J = 30.7, 11.7 Hz, 2H), 3.06 (dd, J =

18.5, 9.1 Hz, 1H), 2.78 – 2.43 (m, 2H), 2.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.0,

200.4, 137.6, 129.6, 128.6, 126.3, 102.2, 98.2, 83.7, 71.0, 39.8, 30.6.

(2R,4aS,8aS)-2-Phenyl-4a,5-dihydro-4H-benzo[d][1,3]dioxin-6(8aH)-one (43): To a

stirred solution of above aldehyde 39 in dry DCM (20 mL) was added DBU

(289 mg, 0.28 mL, 1.9 mmol, 1.0 equiv) at room temperature. The resulting

solution was stirred overnight followed by the addition of MsCl (654 mg, 5.7

mmol, 3 equiv) and triethylamine (1.73 g, 2.32 mL, 17.2 mmol, 9 equiv).

The mixture was stirred for about 4 h until TLC showed full conversion. The

Chapter 5

116

mixture was quenched with a saturated aqueous NH4Cl solution (20 mL) and the layers

were separated. The aqueous layer was washed with ether (3 x 10 mL) and the organic

layers were dried over anhydrous Na2SO4, filtered, concentrated and the crude product

was purified by flash chromatography (eluent pentane/ether) to give 43 as colorless oil

(179 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.24 (m, 5H), 6.87 (dd, J =

10.0, 5.7 Hz, 1H), 6.12 (d, J = 10.0 Hz, 1H), 5.53 (s, 1H), 4.49 (dd, J = 5.7, 2.9 Hz, 1H),

4.17 (dd, J = 12.0, 2.9 Hz, 1H), 4.01 (d, J = 11.9 Hz, 1H), 3.15 (dd, J = 16.6, 13.5 Hz,

1H), 2.38 (dd, J = 16.6, 4.2 Hz, 1H), 2.07 – 1.90 (m, 1H); 13C NMR (101 MHz, CDCl3) δ

199.8, 142.7, 137.7, 132.8, 129.2, 128.4, 126.1, 101.9, 70.6, 69.9, 37.1, 32.5. HRMS

(ESI+) calculated for C14H15O3:231.1016, found: 231.1011. [α]D20 = +112.0 (c = 0.1,

CHCl3).

Triethyl(((2R,4aS,8aS)-2-phenyl-4a,8a-dihydro-4H-benzo[d][1,3]dioxin-6-yl)oxy)sila

ne (50): To a stirred solution of ketone 43 (20 mg, 0.087 mmol, 1 equiv) in 4 mL of dry

DCM was added TESOTf (30.0 mg, 0.113 mmol, 1.3 equiv) and

triethylamine (10.5 mg, 0.104 mmol, 1.2 equiv) at 0 oC under nitrogen. The

mixture was warmed to room temperature and stirred for 1 h when TLC

showed full conversion. The reaction was quenched with a saturated aq.

NH4Cl solution (5 mL), and the layers were separated. The aqueous layer

was washed with ether (3 x 5 mL) and the organic layers were dried over anhydrous

Na2SO4, filtered, concentrated to give 50 as colorless oil which was used in the next step

immediately (50 mg, quant. yield). 1H NMR (400 MHz, CDCl3) δ 7.36 (ddd, J = 7.0, 6.4,

2.4 Hz, 5H), 6.07 (dd, J = 9.7, 1.9 Hz, 1H), 6.00 (dd, J = 9.7, 5.7 Hz, 1H), 5.45 (s, 1H),

5.04 (s, 1H), 4.29 (t, J = 5.1 Hz, 1H), 4.22 (d, J = 1.4 Hz, 2H), 2.33 (s, 1H), 0.92 (t, J =

7.9 Hz, 6H), 0.51 (q, J = 7.9 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 148.6, 138.5, 131.4,

128.9, 128.2, 126.3, 124.2, 106.8, 100.5, 70.7, 69.4, 34.8, 5.8, 4.9.

(5S,6S)-6-Allyl-2,2,3,3,9,9,10,10-octamethyl-5-(2-methylprop-1-en-1-yl)-4,8-dioxa-3,

9-disilaundecane (40): To a stirred solution of diol 35 (200 mg, 1.18 mmol, 1 equiv) in

dry dichloromethane (20 mL) was added imidazole (640 mg, 9.4 mmol,

8 equiv) followed by tert-butyl-dimethylsilyl chloride (1.4 mg, 9.4 mmol,

8 equiv), and the resulting white suspension was stirred at room

temperature overnight. The reaction mixture was quenched with 20 mL

of water and extracted with ether (3 x 20 mL). The combined organic layers were dried

over Na2SO4, filtered, concentrated and the crude product was purified by flash

chromatography (eluent pentane/EtOAc) to give 40 as colorless oil (521 mg, quant. yield). 1H NMR (400 MHz, CDCl3) δ 5.94 – 5.73 (m, 1H), 5.26 – 5.11 (m, 1H), 5.11 – 4.94 (m,

OTBSOTBS

Chapter 5

117

2H), 4.55 (dd, J = 9.1, 5.1 Hz, 1H), 3.57 (dt, J = 14.1, 7.0 Hz, 1H), 3.53 – 3.46 (m, 1H),

2.27 (dddd, J = 7.8, 4.8, 3.9, 2.4 Hz, 1H), 2.17 – 2.00 (m, 1H), 1.72 (d, J = 1.2 Hz, 3H),

1.65 (d, J = 1.3 Hz, 3H), 1.54 (ddd, J = 8.8, 5.0, 3.1 Hz, 1H), 0.92 (s, 9H), 0.90 (s, 9H),

0.04 (s, 6H), 0.04 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 138.3, 131.6, 128.0, 115.2,

68.7, 61.5, 48.1, 30.6, 25.7, 25.7, 18.3, 18.2, -3.0, -4.2. HRMS (ESI+) calculated for

C22H46O2Si2Na:421.2934, found: 421.2964. [α]D20 = -2.0 (c = 0.6, CHCl3).

(4S,5S)-5-((tert-Butyldimethylsilyl)oxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-m

ethyloct-6-en-2-one (41): To a stirred solution of alkene 40 (200 mg, 0.5 mmol, 1 equiv)

in DMA/H2O (15 mL, 1/1 v/v) was added palladium dichloride (9 mg,

0.05 mmol, 10 mol%) and Cu(OAc)2-H2O (20 mg, 0.1 mmol, 20 mol%)

at room temperature under 1 atmosphere of oxygen. The reaction mixture

was stirred for 2 d and quenched with a saturated aq. NH4Cl solution (50

mL) when TLC showed full conversion. The layers were separated, the aqueous layer

was washed with ether (3 x 10 mL) and the organic layers were dried over anhydrous

Na2SO4, filtered, concentrated and the crude product was purified by flash

chromatography (eluent pentane/ether) to give 41 as colorless oil (157 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ 5.14 – 5.05 (m, 1H), 4.52 (dd, J = 8.9, 5.5 Hz, 1H), 3.59

(dd, J = 9.8, 5.9 Hz, 1H), 3.48 (dd, J = 9.8, 5.5 Hz, 1H), 2.59 (dd, J = 17.1, 4.7 Hz, 1H),

2.45 (dd, J = 17.1, 8.2 Hz, 1H), 2.14 (d, J = 9.9 Hz, 3H), 2.11 (dt, J = 8.2, 3.8 Hz, 1H),

1.71 (d, J = 1.1 Hz, 3H), 1.64 (d, J = 1.2 Hz, 3H), 0.90 (d, J = 6.2 Hz, 18H), 0.04 (s,

12H); 13C NMR (101 MHz, CDCl3) δ 214.7, 138.1, 133.0, 74.1, 67.8, 49.8, 46.7, 35.9,

31.4, 31.3, 23.9, 23.8, 23.7, 1.4, 0.6, 0.1. HRMS (ESI+) calculated for

C22H46O3Si2Na:437.2878, found: 437.2878. [α]D20 = +2.0 (c = 0.4, CHCl3).

(2R,3S)-2-((tert-Butyldimethylsilyl)oxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-ox

ohexanal (42): To a stirred solution of ketone 41 (20 mg, 0.48 mmol) in DCM was

bubbled O3 at -78 oC. The ozonolysis was finished when the solution

turned blue. Excess dimethyl sulfide (2 mL) was added and the solution

was warmed to room temperature. The mixture was quenched with a

saturated aq. NH4Cl solution (10 mL). The layers were separated, the



chromatography (eluent pentane/ether) to give 42 as colorless oil which was used

immediately for the next step (cyclization). 1H NMR (400 MHz, CDCl3) δ 9.49 (d, J =

1.3 Hz, 1H), 4.09 (dd, J = 4.1, 1.4 Hz, 1H), 3.76 (dd, J = 9.8, 4.1 Hz, 1H), 3.42 (dd, J =

9.8, 5.3 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.54 – 2.43 (m, 1H), 2.37 (dd, J = 17.6, 6.4 Hz,

OTBSOTBS

O

OTBSOTBS

O

O

Chapter 5

118

1H), 2.11 (s, 3H), 0.87 (d, J = 17.4 Hz, 18H), 0.03 (dd, J = 12.9, 5.5 Hz, 12H); 13C NMR

(101 MHz, CDCl3) δ 207.4, 203.6, 113.7, 85.6, 61.1, 40.7, 39.9, 30.5, 25.8, 25.7, 18.1,

-4.7, -5.1, -5.5, -5.6.


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Prod., 2001, 64, 645. (c) H. Zhang, R. J. Capon, Org. Lett., 2008, 10, 1959. (d) H. Zhang, J. M.

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21. N. Toyooka, M. Okumura, H. Nemoto, J. Org. Chem., 2002, 67, 6078–6081.

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Chapter 5

120

Chapter 6

121

Chapter 6

Total Synthesis of (S)‐(–)‐zearalenone

In this chapter the catalytic asymmetric synthesis of (S)-(–)-zearalenone is described. The

copper-catalyzed asymmetric allylic alkylation is the key strategic element in this

synthesis.

Parts of this chapter have been published: M. P. Baggelaar, Y. Huang, B. L. Feringa, F. J.

Dekker, A. J. Minnaard, Bioorg. Med. Chem. 2013, In Press.

Chapter 6

122

6.1 Introduction

Resorcylic acid lactones are mycotoxins produced by various strains of fungi via

polyketide biosynthesis. These medium-sized macrocyclic lactones exhibit a wide variety

of interesting biological activities,1 among which selective kinase inhibition has been

characterized very well.2 Zearalenone (Figure 1), probably the best known member of the

resorcylic acid lactones, was first isolated from Gibberella zeae in 19623 and four years

later its structure was elucidated.4 It shows estrogen agonistic properties most likely

because its macrocycle can adopt a conformation that is similar to that of steroids.1e Also

of interest, is the fact that related 6-alkyl salicylates inhibit histone acetyl transferase

activity.5 In addition, zearalenone has been shown to exhibit antibacterial, uterotropic and

anabolic activity.3,6 We envisioned that the salicylate core structure in zearalenone could

provide lipoxygenase inhibitory activity for this compound,7 which has been indeed

observed in this study.

Figure 1. Structure of 17‐Estradiol and Zearalenone.

6.2 Biosynthesis of zearalenone

Zearalenone is synthesized via a polyketide pathway by several fungi.8 In the

biosynthesis (Figure 2), two different proteins (ZEA 1 and ZEA 2) are involved.

Condensation of one acetyl-CoA with 5 malonyl-CoA catalyzed by enzyme ZEA 2 gave

the intermediate 4. Intermediate 4 was condensed with 3 malonyl-CoA catalyzed by

enzyme ZEA 1 to form intermediate 5. After aldol reaction, aromatization and lactone

formation, zearalenone 1 was formed.

Chapter 6

123

Figure 2. Biosynthesis of zearalenone 1.

6.3 Previous synthesis of zearalenone.

Many of the synthetic routes to zearalenone 1 either lead to the racemate9 or are based on

natural chiral starting materials10 or on chiral auxiliaries.11 Some groups used kinetic

resolution or an enzymatic approach to obtain the chiral building blocks.12 In 1998 the

group of Nicolaou reported a solid phase synthesis of zearalenone 110d using a novel

cyclorelease mechanism.13

Figure 3. Release of substrate from polymer.

Most solid-phase methods employ a heteroatom that links the substrate to the polymer

support.14 The substrate is released from the polymer by deprotecting the heteroatom,

however, the heteroatom remains in the substrate (Figure 3, A). Recently this method was

Chapter 6

124

replaced by ring closing metathesis and Stille coupling as shown by the group of

Nicolaou (Figure 3, B and C). Oxidation of Merrifield resin 2 (Figure 4) using K2CO3

and DMSO gave the corresponding aldehyde. Olefination of the above aldehyde gave

vinyl resin 3. Radical reaction of vinyl resin 3 with nBu2SnHCl (prepared from

nBu2SnH2 and nBu2SnCl2) afforded polystyrene-di-n-butyltin chloride (PBTC) 4 in 90%

overall yield.

Figure 4. Synthesis of polymer‐supported PBTC.

Sn

nBunBu

Cl

4

LiOTBS

Sn

nBunBu

6

5

OTBS

1. TBAF

2. NCS, Me2S

SnnBu

nBu

7 O

TBSOMgBr

81.

2. NCS, Me2S Sn

nBunBu

9 O

TBSO1. TBAF

O

MEMO

OH

O

I

MEM

2.

10

O

O

OO

MEMO

MEM

I

SnnBu nBu

11

1. Pd(PPh3)4

2. HCl

OH

HO

O

O

O

1

PPh3, DEAD

Figure 5. Solid‐phase total synthesis of (S)‐zearalenone 1 by a cyclorelease mechanism

that uses the Stille coupling strategy.

Displacement of the chloride from PHTC 4 by vinyl lithium 5 gave product 6 in 87%

yield. Removal of the TBS group to the corresponding free alcohol followed by oxidation

using NCS and Me2S gave the aldehyde 7 in 92% overall yield. Addition of Grignard

reagent 8 to aldehyde 7 gave the corresponding secondary alcohol which was followed

by Corey-Kim oxidation to give ketone 9 in 97% overall yield. Removal of the TBS

group to the free alcohol followed by Mitsunobu reaction of carboxylic acid 10 gave the

Chapter 6

125

desired product 11 in 76% overall yield. Palladium catalyzed cyclorelease, after

deprotection, gave (S)-zearalenone 1 in 40% overall yield.

In order to develop a short catalytic route with precise control over the absolute

configuration in this important class of compounds, a catalytic approach is reported here

for the synthesis of (S)-zearalenone using highly enantioselective copper-catalyzed

asymmetric hetero allylic alkylation15 as the key step.

6.4 Retrosynthetic analysis

Figure 6. Retrosynthesis of zearalenone 1.

In our retrosynthetic analysis (Figure 6), the macrocycle 1 was planned to be formed not

by macrolactonization, but by ring-closing metathesis to access the E-double bond. In

this way, the starting material for this ring-closing reaction, 12, can be prepared from

acid fluoride 13 and alcohol 14 which could be obtained from ester 15 by

copper-catalyzed asymmetric allylic alkylation recently developed in our group as

described in chapter 2.


The synthesis started with a Vilsmeier-Haack reaction16 of commercially available

bromide 16 to afford aldehyde 17 in 82% yield (Figure 7). Initial Stille cross coupling17

using Pd2dba3, CuI in NMP resulted in no conversion. Employing THF as the solvent,

product 18 could be obtained in 50% yield. The best yield was provided by Pd(PPh3)4

Chapter 6

126

without any copper additive in toluene. Subsequent Pinnick oxidation16 of aldehyde 18

gave acid 19 in 80% yield followed by fluorination using cyanuric fluoride18 to acid

fluoride 13.

Figure 7. Synthesis of acid fluoride 13.

For the second building block 24, the synthesis started with the preparation of ketone 22.

Alkylation19 (Figure 8) of ketoester 20 using 1-bromo-3-butene gave product 21 in 69%

yield and the product was still contaminated with di-alkylated product. Hydrolysis and

subsequent decarboxylation resulted in 22. Due to the impurities in the final product

another route was tested.

Figure 8. First route towards the synthesis of ketone 22.

Figure 9. Second route towards the synthesis of ketone 22.

Copper catalyzed addition of the Grignard reagent20 to acid chloride 23 resulted in ketone

22 which was transferred into hydrazone21 24 for the subsequent C-C bond formation.

Chapter 6

127

Figure 10. Synthesis of building block 31.

The stereogenic center was installed by copper-catalyzed asymmetric allylic alkylation of

25 recently developed in our group; ester 15 was obtained in high yield and with

excellent enantioselectivity. Hydrolysis followed by protection gave alkene 26 which was

used for hydroboration to alcohol 27 using 9-BBN in high yield and regioselectivity.

Subsequent iodination gave iodide 28 in 88% yield followed by coupling22 with

hydrazone 24, after hydrolysis, gave 29 in 81% yield. Before removal of the TBDPS

group the ketone had to be protected, as without this modification the compound would

suffer loss of enantiopurity by a reversible intramolecular hydride shift as already

reported in 1968 by Wendler et al.9f Protection of the ketone provided 30 followed by

removal of the silane group using TBAF finished the synthesis of the other part.

Chapter 6

128

HOOO

O

O

O

FO

O

OOO

OKHMDS

THF, 0oC

82%1331 32

+

O

OO

O

O

O

O

OO

O

O

Grubbs 2nd

toluene, 80 oC

88%

pTsOH, acetone/H2O

40 oC, 83%

33 34

OH

HO

O

O

O

AlI3, TBAIphloroglucinol5 oC, benzene

63%

OH

OHHO

phloroglucinol(S)-(-)-Zearalenone 1

Figure 11. Final synthesis of zearalenone 1.

Ester formation23 using acid fluoride 13 and alcohol 31 gave alkene 32. Compound 32

was then subjected to alkene metathesis12b catalyzed by the Grubbs second generation

catalyst to E-alkene 33. Removal of the acetal using p-TsOH and demethylation using

AlI3, TBAI and phloroglucinol (iodine scavenger) completed the total synthesis and gave

zearalenone 1 as the final product. The spectroscopic data were in agreement with the

reported data.12d

6.6 Biological studies

Figure 12. Activity of LOX‐5 at different concentrations of zearalenone.

Chapter 6

129

Lipoxygenases inhibition by (S)-(-)-Zearalenone was investigated using a

spectrophotometric assay for the conversion of linoleic acid into hydroperoxy

eicosatetraenoic acid (HPETE) by the group of Dekker at the faculty of mathematics and

natural sciences (FWN). An inhibitory concentration 50% (IC50) of 51 +/- 2 μM was

observed for inhibition of soybean lipoxygenase-1 (SLO-1), which indicates a modest

inhibitory potency. Figure 12 depicts the activity at several different concentrations. To

the best of our knowledge, no LOX-5 inhibition for this type of molecules has been

reported.

6.7 Conclusion

In summary, we have completed the total synthesis of (S)-(-)-zearalenone 1 using

catalytic asymmetric allylic substitution, Stille cross coupling and RCM as key steps.

Asymmetric allylic alkylation was the step in the synthesis used to obtain the chiral

allylic alcohol building block. The new synthetic route is currently explored in the

preparation of other biologically active resorcylic acid lactones.




and distilled prior to use. Column chromatography was performed on silica gel

(SiliaFlash®60, 230-400 mesh). TLC was performed on silica gel 60/Kieselguhr F254.



spectrometer in CDCl3 unless stated otherwise. Chemical shifts are reported in values




High resolution mass spectra (HRMS) were recorded on an AEI-MS-902 and a FTMS



g/100 mL).

Chapter 6

130

2-Bromo-4,6-dimethoxybenzaldehyde (17):16 POCl3 (3.26 mL, 34.8 mmol) was

carefully added to a solution of 16 (3.00 g, 13,9 mmol) in DMF (7.2 mL)

at 0 oC. The mixture was heated to 100 oC and stirred for 4 h. The

reaction mixture was cooled to rt. The brownish oil was poured on ice

and left overnight. The precipitate was filtered and then dissolved in

toluene. The solvent was removed under reduced pressure and the crude product was

purified by flash chromatography (eluent pentane/ether) to give 17 as yellow solid (2.83

g, 83%). 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1 H), 6.74 (d, J = 2.2 Hz, 1 H), 6.40 (d,

J = 2.2 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ 189.2, 164.5,

163.7, 127.4, 116.9, 111.7, 98.2, 56.2, 56.0.

4,6-Dimethoxy-2-vinyl-benzaldehyde (18): To a stirred solution of 17 (450 mg, 1.8

mmol) in toluene (25 mL) was added Pd(PPh3)4 (21 mg, 0.018 mmol, 1

mol%) and tributyl(vinyl)tin (0.86 g, 2.7 mmol) at rt. The mixture was

heated to 100 oC and stirred for 8 h followed by the addition of 25 mL of

aq. KF solution (4 M). The layers were separated and the organic layer

was filtered over celite. The solvent was removed under reduced pressure and purified by

flash chromatography (eluent pentane/ether) to give 18 as yellow solid (295 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1 H), 7.58 (dd, J = 17.4, 10.9 Hz, 1 H), 6.61 (d, J

= 2.2 Hz, 1 H), 6.41 (d, J = 2.3 Hz, 1 H), 5.63 (dd, J = 17.4, 1.4 Hz, 1 H), 5.38 (dd, J =

10.9, 1.4 Hz, 1 H), 3.89 (s, 6 H). 13C NMR (100 MHz, CDCl3) δ 190.5, 164.8, 164.8,

143.6, 136.6, 117.5, 116.4, 104.5, 97.5, 56.0, 55.7. HRMS (ESI+): m/z [M+H]+ calc. for

C11H13O3: 193.0859; found: 193.0857.

4,6-Dimethoxy-2-vinyl-benzoic acid (19): To a stirred solution of 18 (600 mg, 3.12

mmol) in t-BuOH/THF=1:1 (30 mL) was added 2-methyl-2-butene

(2.20 g, 31.2 mmol), NaClO2 (850 mg, 9.4 mmol) and NaH2PO4

(1.13 g, 9.4 mmol) dissolved in water (7 mL) at rt. The mixture was

stirred for 3 h. The solvents were removed under reduced pressure.

The residue was dissolved in H2O and acidified with aq. HCl. The water layer was

extracted with CH2Cl2 (3x 20 mL). The combined organic layers were collected, dried

over anhydrous Na2SO4, concentrated and purified by flash chromatography (eluent

pentane/ethyl acetate) to give 19 as white solid (550 mg, 85%). 1H NMR (400 MHz,

DMSO) δ 6.77 (d, J = 2.0 Hz, 1 H), 6.65 (dd, J = 17.4, 11.0 Hz, 1 H), 6.56 (d, J = 2.0 Hz,

1 H), 5.87 (d, J = 17.4 Hz, 1 H), 5.35 (d, J = 11.1 Hz, 1 H), 3.82 (s, 3H), 3.76 (s, 3 H). 13C NMR (100 MHz, CD2Cl2) δ 172.5, 167.0, 163.5, 146.5, 140.3, 120.8, 116.3, 108.7,

102.5, 60.9, 60.0. HRMS (ESI+): m/z [M+H]+ calc. for C11H13O4: 209.0808; found:

O

O Br

O

O

O

O

O

O

O

OH

Chapter 6

131

209.0805.

2,4-Dimethoxy-6-vinylbenzoyl fluoride(13): To a stirred solution of 19 (40 mg, 0.19

mmol) in CH2Cl2 (3 mL) was added pyridine (45 mg, 0.57 mmol) and

cyanuric fluoride (39 mg, 0.29 mmol) at 0 oC. The mixture was stirred

for 1 h. A few drops of water were added and the mixture was diluted

with 3 mL of CH2Cl2. 2 mL water was added and the water layer was

extracted with CH2Cl2 (3x 5 mL). The combined organic layers were collected, dried over

anhydrous Na2SO4, concentrated and purified by flash chromatography (eluent

pentane/ethyl acetate) to give 13 as white solid (34.1 mg, 85%). 1H NMR (400 MHz,

CDCl3) δ 6.99 (ddd, J = 17.2, 10.9, 3.0 Hz, 1 H), 6.66 (s, 1 H), 6.42 (d, J = 2.1 Hz, 1 H),

5.70 (d, J = 17.2 Hz, 1 H), 5.40 (d, J = 10.9 Hz, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H). 13C

NMR (100 MHz, CDCl3) δ 163.9, 161.1, 158.5, 155.0, 142.6, 134.5, 118.5, 103.6

(JC-F=2.2 Hz, 98.1, 56.3, 55.7. 19F NMR (400 MHz, CDCl3) δ –147.52. HRMS (ESI+):

m/z [M+H]+ calc. for C11H11O3: 191.0703; found: 191.0702.

Hept-6-en-2-one (22):20 To a stirred solution of acetyl chloride (0.96 mL, 13.5 mmol) in

dry THF (17.5 mL) at 0oC under nitrogen was added copper(I) iodide

(129 mg, 0.68 mmol) and pent-4-en-1-ylmagnesium bromide (22.0 mL,

0.59 mM) dropwise over 1 h, prepared from 5-bromopent-1-ene (2.10 g, 13.5 mmol) and

magnesium turnings (400 mg, 16.5 mg). The mixture was subsequently stirred for

another 1h after which the ice/salt bath was removed. The reaction mixture was quenched

with a saturated aq. NH4Cl and extracted with DCM (3x 30 mL). The combined organic

layers were collected, dried over anhydrous Na2SO4, concentrated and purified by flash

chromatography (eluent pentane/ether) to give 22 as colorless oil (1.2 g, 78%). 1H NMR

(400 MHz, CDCl3) δ 5.84 – 5.68 (m, 1 H), 5.00 (m, 2 H), 2.43 (t, J = 7.4 Hz, 2 H), 2.13

(s, 3 H), 2.06 (q, J = 7.3 Hz, 2 H), 1.68 (p, J = 7.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3)

δ 208.9, 137.9, 115.2, 42.8, 33.0, 29.9, 22.7.

2-(Hept-6-en-2-ylidene)-1,1-dimethylhydrazone (24):20 To a stirred solution of

N,N-dimethylhydrazine (1.15 g, 18.6 mmol) in EtOH (35 mL) was

added a catalytic amount of acetic acid (18 mg, 0.31 mmol, 5 mol%)

and hept-6-en-2-one 9 (0.700 g, 6.23 mmol) at rt. The mixture was

heated at reflux for 3 h. The solvent was removed under reduced pressure, and the

residue was dissolved in EtOAc. The organic solution was washed with saturated

NaHCO3 and dried over anhydrous Na2SO4. The solvent was removed under reduced

pressure. Vacuum distillation of the residue gave 24 (807 mg, 84%) as a mixture of

O

O

O

F

O

NN

Chapter 6

132

isomers (Z/E= 1/4) according to NMR. 1H NMR (400 MHz, CDCl 3) δ 5.84–5.68 (m, 1

H), 5.08 – 4.86 (m, 2 H), 2.40 (s, 6H major), 2.37 (s, 6H minor), 2.20–2.14 (m, 2 H),

2.08–2.00 (m, 2 H), 1.91 (s, 3H major), 1.89 (s, 3H minor), 1.66 – 1.50 (m, 2 H).

(S)-(But-3-en-2-yloxy)(tert-butyl)diphenylsilane (26): KOH (4.77 g, 85 mmol) was

dissolved in 25 mL of water followed by the addition of 15 (1.5 g, 8.5

mmol). The mixture was stirred for 65 h at room temperature and

extracted with DCM (3x 30 mL). The organic layers were collected and dried over

anhydrous Na2SO4.

To the above solution was added imidazole (2.3 g, 34 mmol) and TBDPSCl (4.5 g, 17

mmol) at 0 oC. The ice bath was removed and the reaction mixture was stirred at rt for 12

h. The reaction mixture was quenched with aq. NaHCO3 and extracted with DCM (3x 30

mL). The combined organic layers were collected, dried over anhydrous Na2SO4,

concentrated and purified by flash chromatography (eluent pentane/DCM) to give 26 as

colorless oil (2.01 g, 77%). [α]D= + 0.8 (c=1.2, CHCl3). 1H NMR (400 MHz, CDCl3) δ

7.79 – 7.61 (m, 4 H), 7.49 – 7.33 (m, 6 H), 5.88 (ddd, J = 17.1, 10.4, 5.4 Hz, 1 H), 5.12

(dt, J = 17.2, 1.6 Hz, 1 H), 4.97 (dt, J = 10.4, 1.5 Hz, 1 H), 4.37 – 4.28 (m, 1 H), 1.15 (d,

J = 6.3 Hz, 3 H), 1.13 – 1.06 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ 142.5, 135.9, 135.9,

134.6, 134.2, 129.5, 129.5, 127.5, 127.4, 112.7, 70.4, 27.0, 24.0, 19.3. HRMS (ESI+): m/z

[M+H]+ calc. for C20H26OSi: 310.1753; found: 310.2357.

(S)-3-((tert-Butyldiphenylsilyl)oxy)butan-1-ol (27): To a stirred solution of 26 (800 mg,

2.6 mmol) in dry THF (8 mL) was added 9-BBN (10 mL, 0.5 M

in THF) at 0 oC under nitrogen. The ice bath was removed, and

the mixture was stirred for 4 h at rt. The reaction mixture was cooled to 0 oC, and

quenched with ethanol (10 mL) followed by the addition of aq. NaOH (6.5 mL, 4 M) and

H2O2 (6.5 mL). The mixture was warmed to rt and stirred for 12 h. The reaction mixture

was subsequently heated to 60 oC for 2 h and cooled to rt, diluted with ether (100 mL).

The organic layer was washed with aq. NH4Cl, dried over anhydrous Na2SO4,

concentrated and purified by flash chromatography (eluent pentane/ether) to give 27 as

colorless oil (740 mg, 87%). [α]D = +10.0 (c= 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ

7.77 – 7.67 (m, 4 H), 7.49 – 7.36 (m, 6 H), 4.12 (td, J = 6.2, 4.4 Hz, 1 H), 3.84 (ddd, J =

12.7, 8.4, 4.6 Hz, 1 H), 3.70 (dt, J = 10.7, 5.3 Hz, 1 H), 2.32 – 2.06 (m, 1 H), 1.89 – 1.76

(m, 1 H), 1.66 (dtd, J = 14.2, 5.8, 4.7 Hz, 1 H), 1.10 (d, J = 6.2 Hz, 3 H), 1.09 – 1.04 (m,

9 H). 13C NMR (100 MHz, CDCl3) δ 135.9, 135.8, 134.2, 133.7, 129.8, 129.7, 127.7,

127.5, 68.7, 59.9, 40.7, 27.0, 23.0, 19.1. HRMS (ESI+): m/z [M+Na]+ calc. for

C20H28O2SiNa: 351.1751; found: 351.1754.

TBDPSO

TBDPSO OH

Chapter 6

133

(S)-tert-Butyl((4-iodobutan-2-yl)oxy)diphenylsilane (28): To a stirred solution of

imidazole (296 mg, 4.36 mmol) and PPh3 (674 mg, 2.57 mmol) in

dry DCM (15 mL) was added iodine (653 mg, 2.57 mmol) at 0 oC.

The mixture was stirred for 30 min followed by the addition of 27 dissolved in dry DCM

(10 mL). The mixture was warmed to rt and stirred for 2h. The reaction mixture was

quenched with a saturated aq. NH4Cl and extracted with DCM (3x 30 mL). The combined

organic layers were collected, dried over anhydrous Na2SO4, concentrated and purified

by flash chromatography (eluent pentane/ether) to give 28 as colorless oil (760 mg, 88%).

[α]D = – 7.3 (c=1.3 CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.64 (m, 4 H), 7.49 –

7.33 (m, 6 H), 3.99 – 3.86 (m, 1 H), 3.21 (t, J = 7.4 Hz, 2 H), 2.07 (td, J = 14.1, 6.9 Hz, 1

H), 1.94 (dtd, J = 14.1, 7.7, 4.5 Hz, 1 H), 1.10 – 1.00 (m, 12 H). 13C NMR (100 MHz,

CDCl3) δ 135.9, 134.5, 133.8, 129.7, 129.5, 127.6, 127.5, 69.8, 43.5, 27.0, 22.9, 19.3, 2.4.

HRMS (ESI+): m/z [M+Na]+ calc. for C20H28IOSiNa: 439.0982; found: 439.0952.

(S)-10-((tert-Butyldiphenylsilyl)oxy)undec-1-en-6-one (29): To a stirred solution of 14

(320 mg, 2.05 mmol) in dry THF (40 mL) was

added dropwise n-BuLi (1.3 mL, 2.05 mmol) at 0 oC. The mixture was stirred for 1 h and warmed to rt

followed by the addition of 28 dissolved in 20 mL of dry THF. After stirring about 4h the

reaction mixture was quenched with 2 M HCl and stirred overnight. The mixture was

extracted with DCM (3x 30 mL). The combined organic layers were collected, dried over


pentane/ether) to give 29 as colorless oil (465 mg, 81 %. [α]D= –13.2 (c= 1.3, CHCl3). 1H

NMR (400 MHz, CDCl3) δ 7.71-7.64 (m, 4 H), 7.47 – 7.31 (m, 6 H), 5.77 (ddt, J = 17.0,

10.2, 6.7 Hz, 1 H), 5.08 – 4.93 (m, 2 H), 3.93 – 3.76 (m, 1 H), 2.34 (t, J = 7.4 Hz, 2H),

2.26 (t, J = 7.3 Hz, 2 H), 2.04 (dd, J = 14.3, 7.1 Hz, 2 H), 1.72 – 1.62 (m, 2 H), 1.61 –

1.50 (m, 2 H), 1.50 – 1.32 (m, 2 H), 1.07 (d, J = 8.1 Hz, 12 H). 13C NMR (100 MHz,

CDCl3) δ 210.9, 138.0, 135.9, 135.9, 134.8, 134.4, 129.5, 129.4, 127.5, 127.4, 115.2,

69.2, 42.8, 41.7, 38.8, 33.1, 27.0, 23.1, 22.8, 19.6, 19.3. HRMS (ESI+): m/z [M+Na]+ calc.

for C27H38O2SiNa: 445.2533 found: 445.2534.

(S)-tert-Butyl ((5-(2-(pent-4-en-1-yl)-1, 3-dioxolan-2-yl) pentan-2-yl)oxy)diphenyl

silane (30): To a stirred solution of 29 (275 mg, 0.65 mmol) in benzene (6 mL) was

added pTsOH•H2O (5.0 mg, 0.026 mmol), ethylene

glycol (1.20 g, 19.5 mmol) and a few molecular

sieves at rt. The mixture was warmed to 80 oC and

TBDPSO I

TBDPSO

O

TBDPSOOO

Chapter 6

134

stirred for 48 h. The reaction mixture was cooled to rt followed by the addition of EtOAc,

a drop of triethylamine and aq. NaHCO3. The mixture was extracted with DCM (3x 30

mL). The combined organic layers were collected, dried over anhydrous Na2SO4,

concentrated and purified by flash chromatography (eluent pentane/ether) to give 30 as

colorless oil (227 mg, 75%. [α]D = –6.5 (c= 2.8, CHCl3). 1H NMR (400 MHz, CDCl3) δ

7.68 (d, J = 7.9 Hz, 4 H), 7.46 – 7.29 (m, 6H), 5.86 – 5.71 (m, 1 H), 4.98 (ddd, J = 13.7,

11.2, 1.1 Hz, 2 H), 3.95 – 3.76 (m, 5 H), 2.04 (q, J = 6.9 Hz, 2 H), 1.57– 1.23 (m, 10 H),

1.13 – 0.99 (m, 12 H). 13C NMR (100 MHz, CDCl3) δ 138.8, 136.0, 135.1, 134.7, 129.6,

129.5, 127.6, 127.5, 114.7, 111.8, 69.7, 65.0, 39.8, 37.3, 36.8, 34.1, 27.2, 23.4, 23.3, 19.8,

19.4. HRMS (ESI+): m/z [M+H]+ calc. for C29H43O3Si: 467.2976; found: 467.2964.

(S)-5-(2-Pent-4-enyl-[1,3]dioxolan-2-yl)-pentan-2-ol (31): To a stirred solution of 30

(98 mg, 0.21 mmol) in dry THF (4 mL) was added TBAF

(0.42 mL, 0.42 mmol, 1 M in THF) at rt. After stirring for

48 h the reaction mixture was quenched with a saturated

aq. NH4Cl and extracted with DCM (3x 30 mL). The combined organic layers were

collected, dried over anhydrous Na2SO4, concentrated and purified by flash

chromatography (eluent pentane/ether) to give 31 as colorless oil (42.4 mg, 88%). [α]D =

+ 5.4 (c = 1.7, CHCl3). 1H NMR (400 MHz, CDCl3) δ 5.79 (ddt, J = 16.9, 10.2, 6.7 Hz, 1

H), 5.07 – 4.85 (m, 2 H), 3.99 – 3.87 (m, 4 H), 3.79 (m, 1 H), 2.04 (q, J = 7.1 Hz, 2 H),

1.68 – 1.54 (m, 4 H), 1.52 – 1.32 (m, 7 H), 1.18 (d, J = 6.2 Hz, 3 H). 13C NMR (100

MHz, CDCl3) δ 138.8, 114.8, 111.8, 68.1, 65.1, 39.6, 37.1, 36.7, 34.0, 23.6, 23.3, 20.1.

HRMS (ESI+): m/z [M+H]+ calc. for C13H25O3: 229.1798; found: 229.1795.

(S)-5-(2- (Pent-4-en-1-yl)- 1, 3-dioxolan-2-yl) pentan-2-yl-2, 4-dimethoxy-6- vinyl

benzoate (32): To a stirred solution of 31 (0.22 mmol, 50.0 mg) in dry THF (3mL) was

added KHMDS (44 µL, 0.5 M, 0.22 mmol) at

0oC under nitrogen. The mixture was stirred

for an additional 10 min followed by the

addition of acid fluoride 13 (0.13 mmol, 25

mg) dissolved in THF (1 mL). The mixture was stirred for 2h. The reaction mixture was

quenched with a saturated aq. NH4Cl and extracted with DCM (3x 30 mL). The combined

organic layers were collected, dried over anhydrous Na2SO4, concentrated and purified

by flash chromatography (eluent pentane/ether) to give 32 as colorless oil (48 mg, 82%).

[α]D = + 11.2 (c = 1.6, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.73 (dd, J = 17.3 Hz, 10.9,

1 H), 6.63 (d, J = 2.1 Hz, 1 H), 6.38 (d, J = 2.1 Hz, 1 H), 5.83-5.73(m, 1 H), 5.70 (d, J =

17.3 Hz, 1 H), 5.31 (d, J = 11.0 Hz, 1 H), 5.21-5.12(m, 1 H), 5.04 – 4.88 (m, 2 H), 3.91 (s,

HOOO

OOOOO

O

Chapter 6

135

4 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 2.04 (q, J = 7.1 Hz, 2 H), 1.78 – 1.37 (m, 10 H), 1.32 (d,

J = 6.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ 167.5, 161.2, 157.9, 138.6, 137.3, 133.8,

116.9, 116.7, 114.6, 111.5, 101.3, 98.2, 71.9, 64.9, 55.9, 55.4, 36.9, 36.6, 36.1, 33.9, 23.1,

20.1, 19.8. HRMS (ESI+): m/z [M+Na]+ calc. for C24H34O6Na: 441.2248; found:

441.2247.

Zearalenone dimethyl ether ethylene glycol (33): To a stirred solution of 32 (67 mg,

0.16 mmol) in toluene (43 mL) was added Grubbs second

generation catalyst {(1,3-bis(2,4,6-trimethyl

phenyl)-2-imidazolidiny lidene) dichloro (phenylmethylene)

(tricyclohexyl phosphine)ruthenium (6.7 mg, 0.17 mmol)

at rt. The resulting solution was heated to 80 oC and stirred

for 4 h. The solvent was removed under reduced pressure. Flash chromatography of the

residue over silica gel using 1:1 pentane-Et2O yielded zearalenone dimethyl ether

ethylene glycol 33 as white solid (55 mg, 88%). [α]D = + 62.6 (c = 1.0, CHCl3). 1H NMR

(400 MHz, CDCl3) δ 6.58 (d, J = 2.0 Hz, 1 H), 6.43 (d, J = 16.2 Hz, 1 H), 6.35 (d, J = 1.9

Hz, 1 H), 6.29 (dt, J = 16.0, 5.6 Hz, 1 H), 5.29 – 5.14 (m, 1 H), 3.91 (s, J = 8.9 Hz, 4 H),

3.82 (s, 3 H), 3.80 (s, 3 H), 2.43-2.33 (m, 1 H), 2.19-2.07 (m, 1 H), 1.91 – 1.76 (m, 2 H),

1.76 – 1.59 (m, 4 H), 1.58 – 1.37 (m, 4 H), 1.34 (d, J = 6.3 Hz, 3 H). 13C NMR (100 MHz,

CDCl3) δ 168.2, 161.0, 157.4, 136.6, 133.0, 126.1, 116.9, 111.8, 101.0, 97.5, 70.8, 64.3,

64.1, 55.9, 55.4, 35.2, 34.8, 33.1, 30.1, 21.2, 20.2, 19.6. HRMS (ESI+): m/z [M+Na]+ calc.

for C22H30O6Na: 413.1935; found: 413.1935.

(S)-(+)-Zearalenone dimethyl ether (34): To a stirred solution of 33 in an acetone/water

mixture (2 mL, 20:1) was added p-TsOH•H2O (1 mg, 0.005

mmol) at rt. The mixture was warmed to 40 oC and stirred

overnight. The reaction mixture was quenched with a

saturated aq. NH4Cl and extracted with DCM (3x 30 mL).

The combined organic layers were collected, dried over


pentane/ethyl acetate) to give 34 as white solid (18.5 mg, 83%). [α]D = + 48.7 (c= 0.85,

CHCl3) [Lit.10c + 47.8 (c= 0.5, CHCl3)]. 1H NMR (400 MHz, CDCl3) δ 6.59 (d, J = 1.8

Hz, 1 H), 6.45 – 6.32 (m, 2 H), 6.08 – 5.92 (m, 1 H), 5.38 – 5.24 (m, 1 H), 3.83 (s, 3 H),

3.80 (s, 3 H), 2.83 – 2.57 (m, 1 H), 2.46-2.24 (m, 3 H), 2.22 – 1.96 (m, 3 H), 1.90 – 1.45

(m, 5 H), 1.33 (d, J = 6.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ 211.5, 167.7, 161.5,

157.8, 136.9, 133.3, 129.2, 116.5, 101.4, 97.9, 71.3, 56.1, 55.6, 44.2, 37.7, 35.3, 31.4,

O

OO

O

O

O

O

OO

O

O

Chapter 6

136

21.9, 21.5, 20.2. HRMS (ESI+): m/z [M+Na]+ calc. for C20H26O5Na: 369.1673; found:

369.1674.

(S)-(-)-Zearalenone (1):12d To a stirred solution of aluminum powder (37.0 mg, 1.37

mmol) in benzene (2.2 mL) was added iodine (130 mg, 0.51

mmol) at rt. The mixture was heated at reflux until it was

colorless. After cooling to 7 oC a few crystals of TBAI were

added followed by the addition of phloroglucinol (19.5 mg,

0.16 mmol) and 34 (11 mg, 0.03 mmol). The suspension

was stirred for 10 min before 40 mL of Na2S2O4 (aq.) was added. The water layer was

extracted with EtOAc (3x 10 mL). The combined organic layers were collected, dried

over anhydrous Na2SO4, concentrated and purified by flash chromatography (eluent

pentane/ethyl acetate) to give (S)-(–)-zearalenone 1 (6.4 mg, 63%) as a white solid. 1H

NMR (400 MHz, CDCl3) δ 7.01 (dd, J = 15.4 Hz, 1.2Hz, 1 H), 6.41 (d, J = 2.6 Hz, 1 H),

6.35 (d, J = 2.5 Hz, 1 H), 5.74 (s, 1 H), 5.72 – 5.62 (ddd, J = 10.4, 5.4 Hz, 1 H), 5.14 –

4.81 (m, 1 H), 2.96 – 2.76 (ddd, J = 12.4, 6.4, 2.8 Hz, 1 H), 2.69 – 2.54 (m, 1 H), 2.42 –

2.32 (m, 1 H), 2.26 – 2.08 (m, 4 H), 1.87 – 1.70 (m, 2 H), 1.70 – 1.56 (m, 3 H), 1.55 –

1.43 (m, 1 H), 1.38 (d, J = 6.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ 211.6, 171.5,

165.6, 160.7, 144.2, 133.3, 132.7, 108.5, 102.6, 73.6, 43.1, 36.8, 34.9, 31.2, 22.4, 21.2,

21.0. HRMS (ESI+): m/z [M+H]+ calc. for C18H23O5: 319.1540; found: 319.1538.

Biological assay

The enzyme soybean lipoxygenase-1 (SLO-1) was obtained from Cayman Chemicals and

linoleic acid was obtained from Sigma. Sodium borate buffer (H3BO3 0.2 M) pH 9.0 was

used as an assay buffer for all SLO-1 inhibition experiments. The enzyme SLO-1 was

diluted 1:4000 using the SLO-1 assay buffer and the inhibitor (S)-(-)-zearalenone (100

mM in DMSO) was diluted using the same buffer to 200 µM. Linoleic acid (20 mM in

EtOH) was diluted with SLO-1 assay buffer to 200 µM. The enzyme (400 µL, 1:4000)

was mixed with the inhibitor (400 µL, 200 µM) and the mixture was incubated for 10

min. Subsequently, linoleic acid (800 µL, 200 µM) was added to give a mixture with 50

µM inhibitor and 100 µM linoleic acid.

Enzyme inhibition was measured by the residual enzyme activity after 10 min incubation

with the inhibitor at room temperature. The enzyme activity was determined by

conversion of lipoxygenase substrate linoleic acid into hydroperoxy eicosatetraenoic acid

(HPETE). The conversion rate was followed by UV absorbance of the conjugated diene

at 234 nm (ε = 25000 M-1cm-1) over a period of 20 min and started 10 sec after the

addition of the substrate linoleic acid. The UV absorbance increase over time was used to

O

OOH

HO

O

Chapter 6

137

determine the enzyme activity. Inhibitory concentration 50% (IC50) was determined by

measuring the enzyme activity using various concentrations of (S)-(-)-zearalenone (12.5,

25, 50 and 100 μM, Figure 12). The average and standard deviation of three experiments

were plotted. Calculations were performed with Excel 2010 and the non-linear curve

fitting (Figure 12) was performed with the Origin 8 software. Fitting a sigmoidal curve

provided for (S)-(-)-zearalenone an IC50 of 51 +/- 2.0 μM.


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English Summary

139

English Summary

English Summary

140

Copper-catalyzed asymmetric allylic alkylation and asymmetric conjugate addition

in natural product synthesis

This thesis described the copper-catalyzed hetero AAA and ACA applied in the total

synthesis of several biologically active molecules. A second part of this thesis aims at the

development of a novel catalytic asymmetric route towards skipped dienes (1,4-dienes)

with a methyl substituted central stereogenic carbon by copper-catalyzed AAA and its

application in the total synthesis of natural product, Phorbasin B.

Figure 1. Structure of Lasiodiplodin.

In chapter 2, the catalytic asymmetric formal synthesis of Lasiodiplodin is described

(Figure 1). The present approach takes maximum benefit of asymmetric catalysis-copper

catalyzed hetero AAA of Grignard reagent which led to excellent enantioselectivity.

sp3-sp2 Suzuki coupling and RCM are applied for the construction of the macrocycle.

OO

O

OOH

OHRasfonin

Figure 2. Structure of Rasfonin.

In chapter 3, a very efficient total synthesis of the apoptosis inducer (–)-rasfonin has been

described (Figure 2). CuBr/JosiPhos catalyzed iterative ACA of MeMgBr has been

employed to install the stereogenic centers in the upper half side chain with excellent

yield and stereoselectivity. The hydroxy-lactone core could be prepared by a subsequent

stereospecific hydroxy-directed Achmatowicz rearrangement followed by an

oxidation-reduction sequence. The synthesis of the lower makes use of the perfect

English Summary

141

transfer of chirality in the conjugate addition to butenolide followed by selective

construction of the E,E-diene-ester part. The availability of an effective route to Rasfonin

now allows to study its role in inhibiting the Ras signaling pathway, provides access to

functional analogs and might lead to the identification of its target protein.

Figure 3. Copper‐catalyzed AAA of diene allylic bromides.

In chapter 4, copper-catalyzed AAA of methylmagnesium bromide as nucleophile

employing prochiral diene allylic bromides as substrates was described (Figure 3). The

reaction leads to important chiral 1,4-diene building blocks with excellent regio- and

enantioselectivity (ee values up to >99%; SN2’/SN2 ratio up to 97:3) in nearly all cases.

Figure 4. Structure of Phorbasin B.

In chapter 5, several attempts towards the synthesis of Phorbasin B have been described

(Figure 4). So far we have achieved the synthesis of the right part (the 1,4-diene unit) in

very high enantioselective manner described in chapter 4. For the left part, we have

achieved the synthesis of the cyclohexyl ring. Further functionalization of the ring is

required in the future.

Figure 5. Structure of Zearalenone.

English Summary

142

In chapter 6, the catalytic asymmetric total synthesis of Zearalenone is described (Figure

5). Copper-catalyzed AAA is the key step in the synthesis to obtain the chiral allylic

alcohol building block. Stille cross coupling and RCM are applied for the construction of

the macrolactone. Biological test of Zearalenone led to a moderate Lipoxygenases

inhibitor with IC50 of 51 +/- 2 μM.

Nederlandse Samenvatting

143



144

De Toepassing van Koper-gekatalyseerde Asymmetrische Allylische Alkylatie en

Asymmetrische Geconjugeerde Additie in de Totaalsynthese van Natuurproducten

In dit proefschrift wordt de koper-gekatalyseerde hetero AAA en ACA toegepast in de

totaalsynthese van een aantal biologisch actieve moleculen. In het tweede deel van dit

proefschrift ligt de focus op een nieuwe katalytische asymmetrische route naar

1,4-dieenen met een methyl gesubstitueerd chiraal koolstofatoom door middel van

koper-gekatalyseerde AAA. Deze nieuwe strategie wordt toegepast in de totaalsynthese

naar het natuurproduct, Phorbasin B.

Figuur 1. Structuur van Lasiodiplodin.

In hoofdstuk 2 van dit proefschrift wordt de formele totaalsynthese van Lasiodiplodin

(Figuur 1) beschreven. De strategie die wordt toegepast maakt optimaal gebruik van de

asymmetrische koper-gekatalyseerde hetero AAA met methylmagnesium bromide. Met

deze methode werd een zeer hoge enantioselectiviteit bereikt. Sp3-sp2 Suzuki koppeling

en ring sluiting-metathese werden gebruikt voor de constructie van de macrocyclische

ring.

Figuur 2. Structuur van (─)‐Rasfonin.

In hoofdstuk 3 wordt een efficiënte synthese naar (─)-Rasfonin (Figuur 2) beschreven.

Dit natuurproduct staat bekend om zijn apoptose inducerende werking. CuBr/JosiPhos

gekatalyseerde iteratieve ACA met methylmagnesium bromide is gebruikt om de stereo

centra met hoge stereoselectiviteit te introduceren. Het hydroxy-lacton kon worden

geconstrueerd door middel van een stereospeciefieke hydroxy-gestuurde Achmatowics

omlegging gevolgd door een oxidatie- en een reductiestap. De synthese van het onderste


145

deel van het molecuul maakt gebruik van geconjugeerde additie aan buteenolide, gevolgd

door de selectieve constructie van het E,E-dieen-ester deel. Deze nieuwe effectieve route

naar (─)-Rasfonin kan helpen bij de bepaling van de rol die het molecuul speelt bij de

inhibitie van het RAS signaal transductie systeem. Ook geeft deze synthetische methode

toegang tot functionele varianten en kan het leiden tot de identificatie van het eiwit dat

wordt geïnhibeerd door het molecuul.

BrR1

R2

R3 CuBr•SMe2 5 mol%TaniaPhos 6 mol%

MeMgBr 1.2 equiv.

DCM, -80 oC, o.n.

R1

R2

R3

R1

R2

R3

+

SN2' SN2

Fe

(S,S)-TaniaPhos

PPh2NPh2P

tot >99% ee97/3 SN2'/SN2

Figuur 3. Koper‐gekatalyseerde AAA van dieenen met allylische bromides.

In hoofdstuk 4 wordt de koper-gekatalyseerde AAA met methylmagnesium bromide als

nucleofiel op een prochiraal dieen met een allylisch bromide als substraat beschreven

(Figuur 3). Deze reactie geeft toegang tot de belangrijke 1,4-dieen bouwstenen met hoge

regio en stereoselectiviteit (ee waardes tot >99%; en een SN2’/SN2 verhouding tot 97:3)

in bijna alle gevallen.

Figuur 4. Structuur van Phorbasin B.

In hoofdstuk 5 worden enkele pogingen voor de synthese van Phorbasin B (Figuur 4)

beschreven. De synthese van het rechter deel (het 1,4-dieen deel) van het molecuul is

voltooid met met hoge enantioselectiviteit, zoals beschreven in hoofdstuk 4. Ook de

cyclohexyl is gesynthetiseerd, maar verdere functionalisering van de zesring is nog nodig

om het volledige molecuul te kunnen synthetiseren.

Figure 5. Structuur van (S)‐(─)‐Zearalenone.


146

Hoofdstuk 6 beschrijft de totaalsynthese van (S)-(─)-Zearalenone (Figuur 5). De

koper-gekatalyseerde AAA die leidt naar het chirale allylische bouwsteen is een cruciale

stap in deze totaalsynthese. Een Stille koppeling werd gebruikt voor de introductie van

een allyl groep op de fenyl ring. De macrocyclysche ring werd gevormd door middel van

ring-sluitende metathese. (S)-(─)-Zearalenone is getest op de inhibitie van lipoxygenase;

het molecuul bleek een redelijke lipoxygenase inhibitor te zijn met een IC50 van 51 ± 2

μM.

147

Acknowledgments

148

Six years! What a long time. I still remember the first day when I came to Netherlands. I

took the train to Groningen at Schiphol, and accidently I arrived at Leeuwarden. I didn’t

know I should change the cars at Zwolle. Anyway I arrived at Groningen around 1 am

finally. The next thing which I was confused about is that I should reserve the taxi when I

called the taxi service number. Fortunately Groningen is not very big and I finally arrived

at my apartment by walking with two big luggages. What a first day!

Netherlands is really a beautiful country, and I am very happy to decide to come instead

of going to England. The quality of higher level education is very good here. Here I

would like to say “thank you” to many people who contributed to my great success in

Netherlands.

First one, Michael Pollard, I remember the first time we met your English almost killed

me, too fast for me at that time. As my first supervisor in Groningen, you taught me a lot

about chemistry, especially synthesis. That’s the time I decided to set my career as a

synthetic organic chemist. I am very glad we had one joint publication later for my

master project. Thanks for your supervision again.

Adri, you are a very knowledged professor in synthesis. I am glad we worked together for

a long period. And I learned a lot from you, especially on total synthesis and paper

writing. I still remember the first manuscript I prepared for asymmetric hydrogenation.

After reading my manuscript, you said to me“your writing is terrible”. And then you

decided to write the paper by yourself. For the experimental part, I don’t remember how

many times we did the correction. At least 5! Maybe around 10! Thanks again for that

although these days you still need to correct my writing a lot.

Ben, as my PhD supervisor, I am always impressed by your ideas. I am really glad to

work with you. I love your motors a lot although I am not working on it. I remember we

had one disagreement about“do we need the second synthesis of …”after the publication

of rasfonin. I know you are looking for novel synthetic routes and higher level

publications. I totally understand that. However, I found one article from nature

chemistry recently and the topic is “does the world really need another synthesis of …”.

And the final answer according to the author is “yes” due to two reasons. One is for the

development of novel methodologies, and the other is to train students. I remember once I

talked with Steve Ley after his lecture. I asked “you spent almost 20 years finishing

Rapamycin and later you published it only on Chem. Eur. J., is it worth?” He answered

“yes”. Personal answer is also “yes” according to my job hunting experience both in

China and States. The employers did not pay too much attention to my publications;

149

however, they cared about the reactions I did and I know and my ability of

accomplishment of complex molecules. Anyway in academia higher level publications

are way more important.

Martín Fañanás-Mastral, I am glad to work with you on the skipped diene and

1,6-addition projects. You are a very talented chemist. Thanks for your help for those two

projects. I hope one day you can really start you own academic career.

I also want to thank Theodora for GC and HPLC before, then HRMS later. Wim for

NMR. Monic for GC and HPLC now. Hans for elemental analysis.

I also want to thank my current lab mates (Maria, Derk Jan, Claudia, Wim, Wiktor, Anja,

Mickel, Anniek), old ones (Bin, Stella, Peter, Celine) and my lovely colleagues, however,

it’s too much to name them all here; I still want to mention several (Milon, Jiawen,

Kuang-Yen, Massimo, Suresh, Valentin, Lili, Xiaoyan, Depeng, Jeffrey, Beatriz, Niek,

Peter, Miriam, Tiziana, Leticia).

Marc, my dear master student and friend, I am so glad to work with you. You are a very

smart guy. I am very happy when you finished the molecule of zearalenone and the paper

is published recently. Excellent work! I hope you can keep being smart at Leiden. Wu

zhongtao and Liu yun, I am glad to have you guys as friends here. I enjoyed a lot when

having dinner together with you. And my friends in my apartment, Yinwang, Wufan,

Zhangliang, Chen tianshu, Fujin, I enjoyed a lot when we were playing Majiang. I am

sorry about the money I won from you although it’s not a lot.

yange

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University of Groningen Copper-catalyzed asymmetric ... · This chapter gives an introduction on copper-catalyzed asymmetric allylic alkylation and ... asymmetric syntheses of the